Substituted indole Mcl-1 inhibitors

ABSTRACT

The present invention provides for compounds that inhibit the activity of an anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) protein. The present invention also provides for pharmaceutical compositions as well as methods for using compounds for treatment of diseases and conditions (e.g., cancer) characterized by the over-expression or dysregulation of Mcl-1 protein.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of U.S. patent application Ser.No. 15/129,042, filed Sep. 26, 2016, which patent application is theUnited States national stage entry, under 35 U.S.C. § 371, ofInternational Patent Application No. PCT/US2015/022841, filed Mar. 26,2015, which claims the claims benefit of U.S. Provisional ApplicationNo. 61/971,023, filed Mar. 27, 2014, the entire contents of each ofwhich are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention pertains to compounds that inhibit the activity ofan anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1)protein, compositions containing the compounds, and methods of treatingcancer involving over-expressed or dysregulated Mcl-1 protein.

BACKGROUND OF THE INVENTION

Abnormal regulation of apoptosis is now recognized to play an importantrole in the development of cancer. The apoptosis pathway can beinitiated by various extracellular and intracellular stresses, includinggrowth factor deprivation, DNA damage, oncogene induction, and cytotoxicdrugs (Danial, N. N. and Korsmeyer, S J. Cell (2004) 116, 205-219). Thedeath signal leads to the oligomerization of the pro-apoptotic proteinsBax and Bak. Upon activation, they permeabilize the mitochondrial outermembrane and release apoptogenic factors into the cytoplasm. Thisprocess is tightly regulated by both pro-apoptotic (Bax, Bak, Bad, Bid,Bim, Bmf, NOXA, PUMA) and anti-apoptotic (Bcl-2, Bcl-xL, Bcl-w, Bcl2-A1,Mcl-1) members of the Bcl-2 family of proteins. Recent data suggeststhat the anti-apoptotic Bcl-2 proteins function to protect the cell fromapoptotic insults, primarily by preventing disruption of mitochondrialouter membrane integrity by binding to the pro-apoptotic proteins asdescribed in Adams, J. M. and Cory S. Oncogene (2007) 26, 1324-1337;Willis, S. N. et al. Science (2007) 315, 856-859. Because tumor cellsare under stress, alterations in their apoptotic signaling pathways arebelieved to be crucial for survival. Recent data implicatesdown-regulated apoptosis in the onset of cancer. Research has shown, forexample, that anti-apoptotic proteins, are over-expressed in many cancercell types as described in Beroukhim, R. et al. Nature (2010) 463,899-905; Zhang J. Y., Nature Reviews Drug Discovery, (2002) 1, 101;Kirkin, V. et al. Biochimica et Biophysica Acta (2004) 1644, 229-249;and Amundson, S. A. et al. Cancer Research (2000) 60, 6101-6110. Thisdysregulation results in the survival of cells that would otherwise haveundergone apoptosis such as cancer cells. This suggests thatneutralizing the function of anti-apoptotic Bcl-2 proteins may offer aneffective strategy for the elimination of cancer cells. In addition,resistance to chemotherapy which is a major cause of treatment failureand poor prognosis in many cancers can be caused by the upregulation ofanti-apoptotic Bcl-2 family proteins.

An important anti-apoptotic member of the Bcl-2 family is Myeloid cellleukemia-1 (Mcl-1). Mcl-1 is one of the most frequently amplifiedanti-apoptotic genes in human cancers including prostate, lung,pancreatic, breast, ovarian, and cervical cancers, as well as melanoma,B-cell chronic lymphocytic leukemia (B-CLL), acute myeloid leukemia(AML) and acute lymphoblastic leukemia (ALL) (Beroukhim et al. Nature(2010) 463, 899-905). Moreover, its overexpression is implicated as aresistance factor for multiple therapies including widely prescribedmicrotubule-targeted agents for breast cancers, such as paclitaxel andvincristine as well as Gemcitabine, a first-line treatment option forpancreatic cancer (Wei et al. Cancer Chemother Pharmacol (2008) 62,1055-1064 and Wertz et al. Nature (2011) 471, 110-114). These datasuggest that Mcl-1 is an important target for a wide variety of cancers.

In many cancer cell types, the cancer cell's survival is attributed tothe dysregulation of the apoptotic pathway caused by the over-expressionof one or more anti-apoptotic Bcl-2 protein family members. Because ofthe important role for Bcl-2 family of proteins in regulating apoptosisin both cancerous and non-cancerous cells, and the inter-cellvariability of Bcl-2 family protein expression, it could be advantageousto have a small molecule inhibitor that selectively targets andpreferably binds to one type or a subset of anti-apoptotic Bcl-2protein(s). A selective compound also may confer certain advantages inthe clinical setting, by providing flexibility to select a dosingregimen to reduce on-target toxic effects in normal cells.

Because Mcl-1 protein is an important Bcl-2 family member associatedwith a number of diseases, there is a need for compounds which bind toand inhibit the activity of Mcl-1 protein.

SUMMARY OF THE INVENTION

In some embodiments, the present invention provides compounds, andpharmaceutically acceptable compositions thereof, that are effective asinhibitors of Mcl-1. Such compounds have the general formula I or II:

or a pharmaceutically acceptable salt thereof, wherein each of L¹, L²,R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is as defined and described inembodiments herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with MCl-1. Such diseases,disorders, or conditions include those described herein.

Compounds provided by this invention are also useful for the study ofMcl-1 in biological and pathological phenomena and the comparativeevaluation of new Mcl-1 inhibitors in vitro or in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION 1. GeneralDescription of Compounds of the Invention

In certain embodiments, the present invention provides inhibitors ofMcl-1. In some embodiments, such compounds include those of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is selected from a covalent bond or an optionally substituted    bivalent straight or branched C₁₋₆ hydrocarbon chain wherein one or    more methylene units are optionally and independently replaced with    -Cy-;-   -Cy- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or 3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   L² is an optionally substituted bivalent straight or branched C₃₋₆    hydrocarbon chain wherein one or two methylene units of L² are    optionally and independently replaced with —O—, —S—, or —N(R′)—, and    wherein two substituents of L² are optionally taken together to form    an optionally substituted bivalent ring selected from 3-8 membered    saturated or partially unsaturated carbocyclylene or 3-8 membered    saturated or partially unsaturated heterocyclylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R′ is independently selected from hydrogen or optionally    substituted C₁₋₄ alkyl;-   R¹ is selected from hydrogen, halogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, —S(O)R^(y), or —S(O)₂R^(y);-   R² is selected from —C(O)-L³-R^(z), —C(O)N(R)-L³-R^(z),    —C(O)N(R)—C(R)₂-L³-R^(z), —C(O)O-L³-R^(z) or —C(O)S-L³-R^(z);-   L³ is selected from a covalent bond or an optionally substituted    bivalent straight or branched C₁₋₈ hydrocarbon chain wherein one or    more methylene units are optionally and independently replaced with    -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—,    —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   R^(z) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur;-   R³ is an optionally substituted ring selected from a 3-8 membered    saturated or partially unsaturated monocyclic carbocyclic ring,    phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having    1-5 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   each of R⁴, R⁵, and R⁶ is independently selected from R, halogen,    —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂,    —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′,    —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   R⁷ is selected from hydrogen, halogen, —CN, —NO₂, —C(O)OR, —OCF₃,    —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂,    —N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR,    —S(O)₂N(R)C(O)N(R)₂, —C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R,    —OC(O)N(R)₂, —C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R,    —N(R)C(O)OR, or —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic or a ring selected from a 3-8 membered    saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, an 8-14    membered bicyclic or polycyclic saturated, partially unsaturated or    aryl ring, a 7-14 membered bicyclic or polycyclic saturated or    partially unsaturated heterocyclic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-14    membered bicyclic or polycyclic heteroaryl ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    and-   optionally R¹ and R², R¹ and R⁷, R⁴ and R⁵, R⁵ and R⁶ and/or R⁶ and    R⁷ are taken together with their intervening atoms to form an    optionally substituted ring selected from a 3-8 membered saturated    or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered    saturated or partially unsaturated heterocyclic ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is selected from a covalent bond or an optionally substituted    bivalent straight or branched C₁₋₆ hydrocarbon chain wherein one or    more methylene units are optionally and independently replaced with    -Cy-;-   -Cy- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or 3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   L² is an optionally substituted bivalent straight or branched C₃₋₆    hydrocarbon chain wherein one or two methylene units of L² are    optionally and independently replaced with —O—, —S—, or —N(R′)—, and    wherein two substituents of L² are optionally taken together to form    an optionally substituted bivalent ring selected from 3-8 membered    saturated or partially unsaturated carbocyclylene or 3-8 membered    saturated or partially unsaturated heterocyclylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R′ is independently selected from hydrogen or optionally    substituted C₁₋₄ alkyl;-   R¹ is selected from hydrogen, halogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, —S(O)R^(y), or —S(O)₂R^(y);-   R² is selected from —C(O)-L³-R^(z), —C(O)N(R)-L³-R^(z),    —C(O)N(R)—C(R)₂-L³-R^(z), —C(O)O-L³-R^(z) or —C(O)S-L³-R^(z);-   L³ is selected from a covalent bond or an optionally substituted    bivalent straight or branched C₁₋₈ hydrocarbon chain wherein one or    more methylene units are optionally and independently replaced with    -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—,    —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   R^(z) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur;-   R³ is an optionally substituted ring selected from a 3-8 membered    saturated or partially unsaturated monocyclic carbocyclic ring,    phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having    1-5 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   each of R⁴, R⁵, and R⁶ is independently selected from R, halogen,    —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂,    —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′,    —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   R⁷ is selected from hydrogen, halogen, —CN, —NO₂, —C(O)OR, —OCF₃,    —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂,    —N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR,    —S(O)₂N(R)C(O)N(R)₂, —C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R,    —OC(O)N(R)₂, —C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R,    —N(R)C(O)OR, or —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic or a ring selected from a 3-8 membered    saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, an 8-14    membered bicyclic or polycyclic saturated, partially unsaturated or    aryl ring, a 7-14 membered bicyclic or polycyclic saturated or    partially unsaturated heterocyclic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-14    membered bicyclic or polycyclic heteroaryl ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    and-   optionally R¹ and R², R¹ and R⁷, R⁴ and R⁵, R⁵ and R⁶ and/or R⁶ and    R⁷ are taken together with their intervening atoms to form an    optionally substituted ring selected from a 3-8 membered saturated    or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered    saturated or partially unsaturated heterocyclic ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound offormula III:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of R⁵, R⁶, R⁸, and R⁹ is independently selected from R,    halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂,    —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′,    —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   each R′ is independently selected from hydrogen or optionally    substituted C₁₋₄ alkyl;-   L⁴ is independently selected from a covalent bond or an optionally    substituted bivalent straight or branched C₁₋₈ hydrocarbon chain    wherein one or more methylene units are optionally and independently    replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—,    —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   -Cy′- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, an 8-10 membered bicyclic arylene or heteroarylene having    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, or an 8-10 membered saturated or partially unsaturated    heterocyclylene having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R^(w) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR,    —C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R; and-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur; and-   R⁷ is selected from hydrogen, halogen, —CN, —NO₂, —C(O)OR, —OCF₃,    —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂,    —N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR,    —S(O)₂N(R)C(O)N(R)₂, —C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R,    —OC(O)N(R)₂, —C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R,    —N(R)C(O)OR, or —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic or a ring selected from a 3-8 membered    saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, an 8-14    membered bicyclic or polycyclic saturated, partially unsaturated or    aryl ring, a 7-14 membered bicyclic or polycyclic saturated or    partially unsaturated heterocyclic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-14    membered bicyclic or polycyclic heteroaryl ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound offormula IV:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of R⁵, R⁶, R¹⁰, R¹¹, and R¹² is independently selected from R,    halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂,    —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′,    —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   each R′ is independently hydrogen or optionally substituted C₁₋₄    alkyl;-   L⁴ is independently selected from a covalent bond or an optionally    substituted bivalent straight or branched C₁₋₈ hydrocarbon chain    wherein one or more methylene units are optionally and independently    replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—,    —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   -Cy′- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, an 8-10 membered bicyclic arylene or heteroarylene having    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, or an 8-10 membered saturated or partially unsaturated    heterocyclylene having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R^(w) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR,    —C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur; and-   R⁷ is selected from hydrogen, halogen, —CN, —NO₂, —C(O)OR, —OCF₃,    —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂,    —N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR,    —S(O)₂N(R)C(O)N(R)₂, —C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R,    —OC(O)N(R)₂, —C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R,    —N(R)C(O)OR, or —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic or a ring selected from a 3-8 membered    saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, an 8-14    membered bicyclic or polycyclic saturated, partially unsaturated or    aryl ring, a 7-14 membered bicyclic or polycyclic saturated or    partially unsaturated heterocyclic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-14    membered bicyclic or polycyclic heteroaryl ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound offormula V:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is selected from a covalent bond or an optionally substituted    bivalent straight or branched C₁₋₆ hydrocarbon chain wherein one or    more methylene units are optionally and independently replaced with    -Cy-;-   Cy- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or 3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   R¹ is selected from hydrogen, halogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, —S(O)R^(y), or —S(O)₂R^(y);-   each of R⁵ and R⁶ is independently selected from R, halogen, —CN,    —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂,    —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′,    —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   each R′ is independently hydrogen or optionally substituted C₁₋₄    alkyl;-   R^(2′) is selected from —C(O)-L⁴-R^(w), —C(O)N(R)-L⁴-R^(w),    —C(O)N(R)—C(R)₂-L⁴-R^(w), —C(O)O-L⁴-R^(w) or —C(O)S-L⁴-R^(w)-   L⁴ is independently selected from a covalent bond or an optionally    substituted bivalent straight or branched C₁₋₈ hydrocarbon chain    wherein one or more methylene units are optionally and independently    replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—,    —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   -Cy′- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic arylene or heteroarylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered saturated or partially unsaturated    heterocyclylene having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R^(w) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR,    —C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur;-   R⁷ is selected from hydrogen, halogen, —CN, —NO₂, —C(O)OR, —OCF₃,    —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂,    —N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR,    —S(O)₂N(R)C(O)N(R)₂, —C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R,    —OC(O)N(R)₂, —C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R,    —N(R)C(O)OR, or —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic or a ring selected from a 3-8 membered    saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, an 8-14    membered bicyclic or polycyclic saturated, partially unsaturated or    aryl ring, a 7-14 membered bicyclic or polycyclic saturated or    partially unsaturated heterocyclic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-14    membered bicyclic or polycyclic heteroaryl ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    and-   optionally R¹ and R^(2′) are taken together with their intervening    atoms to form an optionally substituted ring selected from a 3-8    membered saturated or partially unsaturated carbocyclic ring,    phenyl, a 3-8 membered saturated or partially unsaturated    heterocyclic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur.

In certain embodiments, the present invention provides a compound offormula VI:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of R⁵, R⁶, R⁸, R⁹, and R¹³ is independently selected from R,    halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂,    —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′,    —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   each R′ is independently selected from hydrogen or optionally    substituted C₁₋₄ alkyl;-   n is selected from 1 or 2;-   L⁴ is independently selected from a covalent bond or an optionally    substituted bivalent straight or branched C₁₋₈ hydrocarbon chain    wherein one or more methylene units are optionally and independently    replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—,    —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   -Cy′- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, an 8-10 membered bicyclic arylene or heteroarylene having    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, or an 8-10 membered saturated or partially unsaturated    heterocyclylene having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R^(w) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR,    —C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;    and-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur

In certain embodiments, the present invention provides a compound offormula VII:

-   or a pharmaceutically acceptable salt thereof, wherein:-   each of R⁵, R⁶, and R¹³ is independently selected from R, halogen,    —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂,    —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′,    —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   each R′ is independently hydrogen or optionally substituted C₁₋₄    alkyl;-   R^(2′) is selected from —C(O)-L⁴-R^(w), —C(O)N(R)-L⁴-R^(w),    —C(O)N(R)—C(R)₂-L⁴-R, —C(O)O-L⁴-R^(w) or —C(O)S-L⁴-R^(w)-   L⁴ is independently selected from a covalent bond or an optionally    substituted bivalent straight or branched C₁₋₈ hydrocarbon chain    wherein one or more methylene units are optionally and independently    replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—,    —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   -Cy′- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, an 8-10 membered bicyclic arylene or heteroarylene having    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, or an 8-10 membered saturated or partially unsaturated    heterocyclylene having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R^(w) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR,    —C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R; and-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;    and-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75th Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th Ed., Ed.:Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic or polycyclic hydrocarbon that is completely saturated orthat contains one or more units of unsaturation, but which is notaromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of themolecule. Unless otherwise specified, aliphatic groups contain 1-6aliphatic carbon atoms. In some embodiments, aliphatic groups contain1-5 aliphatic carbon atoms. In other embodiments, aliphatic groupscontain 1-4 aliphatic carbon atoms. In still other embodiments,aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet otherembodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Insome embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”)refers to a monocyclic C3-C6 hydrocarbon that is completely saturated orthat contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule. Suitable aliphatic groups include, but are not limited to,linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynylgroups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen; or a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR+ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, naphthyl, anthracyl and the like,which may be optionally substituted. Also included within the scope ofthe term “aryl,” as it is used herein, is a group in which an aromaticring is fused to one or more non-aromatic rings, such as indanyl,phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, andthe like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 it electrons shared in a cyclic array; and having,in addition to carbon atoms, from one to five heteroatoms. Heteroarylgroups include, without limitation, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Non-limiting examples include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms. When used in reference to a ring atom of aheterocycle, the term “nitrogen” includes a substituted nitrogen. As anexample, in a saturated or partially unsaturated ring having 1-3heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen maybe N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR(as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(◯); —(CH₂)₀₋₄OR^(◯); —O(CH₂)₀₋₄R^(◯), —O—(CH₂)₀₋₄C(O)OR^(◯);—(CH₂)₀₋₄CH(OR^(◯))₂; —(CH₂)₀₋₄SR^(◯); —(CH₂)₀₋₄Ph, which may besubstituted with R^(◯); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(◯); —CH═CHPh, which may be substituted with R^(◯);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(◯); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(◯))₂; —(CH₂)₀₋₄N(R^(◯))C(O)R^(◯);—N(R^(◯))C(S)R^(◯); —(CH₂)₀₋₄N(R^(◯))C(O)NR^(◯) ₂; —N(R^(◯))C(S)NR^(◯)₂; —(CH₂)₀₋₄N(R^(◯))C(O)OR^(◯); —N(R^(◯))N(R^(◯))C(O)R^(◯);—N(R^(◯))N(R^(◯))C(O)NR^(◯) ₂; —N(R^(◯))N(R^(◯))C(O)OR^(◯);—(CH₂)₀₋₄C(O)R^(◯); —C(S)R^(◯); —(CH₂)₀₋₄C(O)OR; —(CH₂)₀₋₄C(O)SR^(◯);—(CH₂)₀₋₄C(O)OSiR₃; —(CH₂)₀₋₄OC(O)R^(◯); —OC(O)(CH₂)₀₋₄SR—,—(CH₂)₀₋₄SC(O)R^(◯); —(CH₂)₀₋₄C(O)NR^(◯) ₂; —(CH₂)₀₋₄C(O)N(R^(◯))S(O)₂R;—C(S)NR^(◯) ₂; —C(S)SR^(◯); —SC(S)SR^(◯), —(CH₂)₀₋₄OC(O)NR^(◯) ₂;—C(O)N(OR)R^(◯); —C(O)C(O)R^(◯); —C(O)CH₂C(O)R^(◯); —C(NOR^(◯))R^(◯);—(CH₂)₀₋₄SSR^(◯); —(CH₂)₀₋₄S(O)R^(◯); —(CH₂)₀₋₄S(O)₂R^(◯);—(CH₂)₀₋₄S(O)₂OR^(◯); —(CH₂)₀₋₄OS(O)₂R^(◯); —S(O)₂NR^(◯) ₂;—S(O)₂N(R)C(O)R^(◯); —(CH₂)₀₋₄S(O)R^(◯); —N(R^(◯))S(O)₂NR^(◯) ₂;—N(R^(◯))S(O)₂R; —N(OR^(◯))R^(◯); —C(NH)NR^(◯) ₂; —P(O)₂R^(◯);—P(O)R^(◯) ₂; —OP(O)R^(◯) ₂; —OP(O)(OR^(◯))₂; —SiR^(◯) ₃; —(C₁₋₄straight or branched alkylene)O—N(R^(◯))₂; or —(C1-4 straight orbranched alkylene)C(O)O—N(R^(◯))₂, wherein each R^(◯) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(◯), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(◯) (or the ring formed by takingtwo independent occurrences of R^(◯) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂S(O)R^(●), —(CH₂)₀₋₂S(O)₂R^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight or branchedalkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●) is unsubstituted orwhere preceded by “halo” is substituted only with one or more halogens,and is independently selected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph,or a 5-6-membered saturated, partially unsaturated, or aryl ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Suitable divalent substituents on a saturated carbon atom of R^(◯)include ═O and ═S.

Suitable divalent substituents on a suitable carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R²))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)R^(●),—C(O)OH, —C(O)OR^(●), —C(O)NR^(●) ₂, —SR^(●), —S(O)R^(●), —S(O)₂R^(●),—NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) is unsubstitutedor where preceded by “halo” is substituted only with one or morehalogens, and is independently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, —C(NR^(†))NR^(†) ₂, or—N(R^(†))S(O)₂R^(†); wherein each R^(†) is independently hydrogen, C₁₋₆aliphatic which may be substituted as defined below, unsubstituted —OPh,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, notwithstanding the definition above, twoindependent occurrences of R^(†), taken together with their interveningatom(s) form an unsubstituted 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —C(O)NR^(●) ₂, —SR^(●), —S(O)R^(●), —S(O)₂R^(●),—NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) is unsubstitutedor where preceded by “halo” is substituted only with one or morehalogens, and is independently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N+(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a 13C- or 14C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

3. Description of Exemplary Embodiments

In some embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is selected from a covalent bond or an optionally substituted    bivalent straight or branched C₁₋₆ hydrocarbon chain wherein one or    more methylene units are optionally and independently replaced with    -Cy-;-   -Cy- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or 3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   R¹ is selected from hydrogen, halogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, —S(O)R^(y), or —S(O)₂R^(y);-   R² is selected from —C(O)-L³-R^(z), —C(O)N(R)-L³-R^(z),    —C(O)N(R)—C(R)₂-L³-R^(z), —C(O)O-L³-R^(z) or —C(O)S-L³-R;-   L³ is independently selected from a covalent bond or an optionally    substituted bivalent straight or branched C₁₋₈ hydrocarbon chain    wherein one or more methylene units are optionally and independently    replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—,    —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   R^(z) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur;-   L² is an optionally substituted bivalent straight or branched C₃₋₆    hydrocarbon chain wherein one or two methylene units of L² are    optionally and independently replaced with —O—, —S—, or —N(R′)—, and    wherein two substituents of L² are optionally taken together to form    an optionally substituted bivalent ring selected from 3-8 membered    saturated or partially unsaturated carbocyclylene or 3-8 membered    saturated or partially unsaturated heterocyclylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R′ is independently selected from hydrogen or optionally    substituted C₁₋₄ alkyl;-   R³ is an optionally substituted ring selected from a 3-8 membered    saturated or partially unsaturated monocyclic carbocyclic ring,    phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having    1-5 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   each of R⁴, R⁵, and R⁶ is independently selected from R, halogen,    —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂,    —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′,    —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   R⁷ is selected from hydrogen, halogen, —CN, —NO₂, —C(O)OR, —OCF₃,    —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂,    —N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR,    —S(O)₂N(R)C(O)N(R)₂, —C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R,    —OC(O)N(R)₂, —C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R,    —N(R)C(O)OR, or —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic or a ring selected from a 3-8 membered    saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, an 8-14    membered bicyclic or polycyclic saturated, partially unsaturated or    aryl ring, a 7-14 membered bicyclic or polycyclic saturated or    partially unsaturated heterocyclic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-14    membered bicyclic or polycyclic heteroaryl ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    and-   optionally R¹ and R², R¹ and R⁷, R⁴ and R⁵, R⁵ and R⁶ and/or R⁶ and    R⁷ are taken together with their intervening atoms to form an    optionally substituted ring selected from a 3-8 membered saturated    or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered    saturated or partially unsaturated heterocyclic ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is selected from a covalent bond or an optionally substituted    bivalent straight or branched C₁₋₆ hydrocarbon chain wherein one or    more methylene units are optionally and independently replaced with    -Cy-;-   -Cy- is an optionally substituted bivalent ring independently    selected from phenylene, 3-8 membered saturated or partially    unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or 3-8 membered saturated or partially unsaturated heterocyclylene    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   R¹ is selected from hydrogen, halogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, —S(O)R^(y), or —S(O)₂R^(y);-   R² is selected from —C(O)-L³-R^(z), —C(O)N(R)-L³-R^(z),    —C(O)N(R)—C(R)₂-L³-R^(z), —C(O)O-L³-R^(z) or —C(O)S-L³-R^(z);-   L³ is independently selected from a covalent bond or an optionally    substituted bivalent straight or branched C₁₋₈ hydrocarbon chain    wherein one or more methylene units are optionally and independently    replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—,    —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—;-   R^(z) is selected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R,    —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x),    —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

-   R^(w) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   R^(y) is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂;-   each R is independently selected from hydrogen or an optionally    substituted group selected from C₁₋₁₂ aliphatic or a ring selected    from a 3-10 membered saturated or partially unsaturated carbocyclic    ring, phenyl, a 6-10 membered bicyclic saturated, partially    unsaturated or aryl ring, a 3-8 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen or sulfur;-   L² is an optionally substituted bivalent straight or branched C₃₋₆    hydrocarbon chain wherein one or two methylene units of L² are    optionally and independently replaced with —O—, —S—, or —N(R′)—, and    wherein two substituents of L² are optionally taken together to form    an optionally substituted bivalent ring selected from 3-8 membered    saturated or partially unsaturated carbocyclylene or 3-8 membered    saturated or partially unsaturated heterocyclylene having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R′ is independently selected from hydrogen or optionally    substituted C₁₋₄ alkyl;-   R³ is an optionally substituted ring selected from a 3-8 membered    saturated or partially unsaturated monocyclic carbocyclic ring,    phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having    1-5 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   each of R⁴, R⁵, and R⁶ is independently selected from R, halogen,    —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂,    —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′,    —N(R′)C(O)OR′, and —N(R′)S(O)₂R′;-   R⁷ is selected from hydrogen, halogen, —CN, —NO₂, —C(O)OR, —OCF₃,    —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂,    —N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR,    —S(O)₂N(R)C(O)N(R)₂, —C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R,    —OC(O)N(R)₂, —C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R,    —N(R)C(O)OR, or —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic or a ring selected from a 3-8 membered    saturated or partially unsaturated carbocyclic ring, phenyl, a 3-8    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, an 8-14    membered bicyclic or polycyclic saturated, partially unsaturated or    aryl ring, a 7-14 membered bicyclic or polycyclic saturated or    partially unsaturated heterocyclic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-14    membered bicyclic or polycyclic heteroaryl ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    and-   optionally R¹ and R², R¹ and R⁷, R⁴ and R⁵, R⁵ and R⁶ and/or R⁶ and    R⁷ are taken together with their intervening atoms to form an    optionally substituted ring selected from a 3-8 membered saturated    or partially unsaturated carbocyclic ring, phenyl, a 3-8 membered    saturated or partially unsaturated heterocyclic ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, the present invention provides a compound of anyone of formulae III, IV, V, VI, and VII, or a pharmaceuticallyacceptable salt thereof, wherein each variable is as defined above anddescribed herein.

As generally defined above, L¹ of formula I, II, or V is selected from acovalent bond or an optionally substituted bivalent straight or branchedC₁₋₆ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy-. In some embodiments, L¹is a covalent bond. In some embodiments, L¹ is an optionally substitutedbivalent straight or branched C₁₋₆ hydrocarbon chain wherein one or moremethylene units are optionally and independently replaced with -Cy-. Insome embodiments, L¹ is an optionally substituted bivalent straight orbranched C₁₋₆ hydrocarbon chain. In some embodiments, L¹ is anoptionally substituted bivalent straight or branched C₁₋₆ hydrocarbonchain wherein one or more methylene units are independently replacedwith -Cy-.

In some embodiments, L¹ is an optionally substituted bivalent straightor branched C₁₋₆ hydrocarbon chain. In some embodiments, L¹ is anoptionally substituted bivalent straight or branched C₂₋₆ hydrocarbonchain. In some embodiments, L¹ is an optionally substituted bivalentstraight or branched C₃₋₆ hydrocarbon chain. In some embodiments, L¹ isan optionally substituted bivalent straight or branched C₄₋₆ hydrocarbonchain. In some embodiments, L¹ is an optionally substituted bivalentstraight or branched C₅₋₆ hydrocarbon chain. In some embodiments, L¹ isan optionally substituted methylene group. In some embodiments, L¹ is anoptionally substituted bivalent C₂ hydrocarbon chain. In someembodiments, L¹ is an optionally substituted bivalent straight orbranched C₃ hydrocarbon chain. In some embodiments, L¹ is an optionallysubstituted bivalent straight or branched C₄ hydrocarbon chain. In someembodiments, L¹ is an optionally substituted bivalent straight orbranched C₅ hydrocarbon chain. In some embodiments, L¹ is an optionallysubstituted bivalent straight or branched C₆ hydrocarbon chain.

In some embodiments, L¹ is an unsubstituted bivalent C₁₋₆ hydrocarbonchain. In some embodiments, L¹ is an unsubstituted bivalent C₂₋₆hydrocarbon chain. In some embodiments, L¹ is an unsubstituted bivalentC₃₋₆ hydrocarbon chain. In some embodiments, L¹ is an unsubstitutedbivalent C₄₋₆ hydrocarbon chain. In some embodiments, L¹ is anunsubstituted bivalent C₅₋₆ hydrocarbon chain. In some embodiments, L¹is an unsubstituted methylene group. In some embodiments, L¹ is anunsubstituted bivalent C₂ hydrocarbon chain. In some embodiments, L¹ isan unsubstituted bivalent C₃ hydrocarbon chain. In some embodiments, L¹is an unsubstituted bivalent C₄ hydrocarbon chain. In some embodiments,L¹ is an unsubstituted bivalent C₅ hydrocarbon chain. In someembodiments, L¹ is an unsubstituted bivalent C₆ hydrocarbon chain.

In some embodiments, L¹ is a substituted bivalent C₁₋₆ hydrocarbonchain. In some embodiments, L¹ is a substituted bivalent C₂₋₆hydrocarbon chain. In some embodiments, L¹ is a substituted bivalentC₃₋₆ hydrocarbon chain. In some embodiments, L¹ is a substitutedbivalent C₄₋₆ hydrocarbon chain. In some embodiments, L¹ is asubstituted bivalent C₅₋₆ hydrocarbon chain. In some embodiments, L¹ isa substituted methylene group. In some embodiments, L¹ is a substitutedbivalent C₂ hydrocarbon chain. In some embodiments, L¹ is a substitutedbivalent C₃ hydrocarbon chain. In some embodiments, L¹ is a substitutedbivalent C₄ hydrocarbon chain. In some embodiments, L¹ is a substitutedbivalent C₅ hydrocarbon chain. In some embodiments, L¹ is a substitutedbivalent C₆ hydrocarbon chain.

In some embodiments, L¹ is a substituted bivalent C₁₋₆ hydrocarbon chainwherein none of the substituents are —N(R)₂ or —N(R)C(O)R. In someembodiments, L¹ is a substituted bivalent C₁₋₆ hydrocarbon chain whereinnone of the substituents are —N(R)₂ or —NHC(O)R.

In some embodiments, L¹ is optionally substituted methylene. In someembodiments, L¹ is —CH₂—. In some embodiments, L¹ is optionallysubstituted —CH₂CH₂—. In some embodiments, L¹ is —CH₂CH₂—. In someembodiments, L¹ is —CH(CH₃)—. In some embodiments, L¹ is —CH(CH₂CH₃)—.In some embodiments, L¹ is —CH(Ph)-. In some embodiments, L¹ is—CH(CH₃)CH₂—. In some embodiments, L¹ is —CH(Ph)CH₂—.

In some embodiments, L¹ is partially unsaturated. In some embodiments,L¹ comprises one or more double bonds. In some embodiments, L¹ is—CH═CH—. In some embodiments, L¹ comprises one or more triple bonds.

As defined generally above, -Cy- of formula I, II, or V is an optionallysubstituted bivalent ring independently selected from phenylene, 3-8membered saturated or partially unsaturated carbocyclylene, 5-6 memberedheteroarylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 3-8 membered saturated or partiallyunsaturated heterocyclylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is optionally substituted phenylene. In someembodiments, -Cy- is substituted phenylene. In some embodiments, -Cy- isunsubstituted phenylene. In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is optionally substituted bivalent 3-8membered saturated or partially unsaturated carbocyclylene. In certainembodiments, -Cy- is optionally substituted bivalent 3-8 memberedsaturated carbocyclylene. In certain embodiments, -Cy- is optionallysubstituted bivalent 3-6 membered saturated carbocyclylene. In certainembodiments, -Cy- is optionally substituted bivalent 3-memberedsaturated carbocyclylene. In certain embodiments, -Cy- is optionallysubstituted bivalent 4-membered saturated carbocyclylene. In certainembodiments, -Cy- is optionally substituted bivalent 5-memberedsaturated carbocyclylene. In certain embodiments, -Cy- is optionallysubstituted bivalent 6-membered saturated carbocyclylene.

In some embodiments, -Cy- is optionally substituted bivalent 5-6membered heteroarylene having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, -Cy- isoptionally substituted bivalent 5-membered heteroarylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy- is optionally substituted bivalent 5-memberedheteroarylene having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, -Cy- is optionallysubstituted bivalent 5-membered heteroarylene having one heteroatomindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, -Cy- is

In certain embodiments, -Cy- is optionally substituted bivalent6-membered heteroarylene having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, -Cy- isoptionally substituted bivalent 6-membered heteroarylene having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is optionally substituted bivalent 3-8membered saturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy- is optionally substituted bivalent 3-8membered saturated heterocyclylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In certain embodiments, -Cy-is optionally substituted bivalent 3-8 membered saturatedheterocyclylene having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, -Cy- is optionallysubstituted bivalent 5-6 membered saturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy- is optionally substituted bivalent 5-6membered saturated heterocyclylene having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In certain embodiments, -Cy-is optionally substituted bivalent 5-membered saturated heterocyclylenehaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In certain embodiments, -Cy- is optionally substituted bivalent6-membered saturated heterocyclylene having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

As defined generally above, R¹ of formula I, II, or V is hydrogen,halogen, R, —OR, —SR, —S(O)R, —S(O)₂R, —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂,—C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,—N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x), —S(O)₂OH, —S(O)R^(y), or—S(O)₂R^(y). In some embodiments, R¹ is hydrogen. In some embodiments,R¹ is not hydrogen. In some embodiments, R¹ is halogen, R, —OR, —SR,—S(O)R, —S(O)₂R, —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R,—N(R)C(O)OR, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH,—C(O)R^(x), —S(O)₂OH, —S(O)R^(y), or —S(O)₂R^(y).

In some embodiments, R¹ is halogen. In some embodiments, R¹ is —F. Insome embodiments, R¹ is —Cl. In some embodiments, R¹ is —Br. In someembodiments, R¹ is —I.

In some embodiments, R¹ is R. In some embodiments, R¹ is R, wherein R isnot hydrogen. In some embodiments, R¹ is optionally substituted C₁₋₁₂aliphatic. In some embodiments, R¹ is optionally substituted C₁₋₆ alkyl.In some embodiments, R¹ is methyl.

In some embodiments, R¹ is —OR. In some embodiments, R¹—SR. In someembodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R. In someembodiments, R¹ is —S(O)₂N(R)₂. In some embodiments, R¹ is —N(R)₂. Insome embodiments, R¹ is —C(O)N(R)₂. In some embodiments, R¹ is —C(O)R.In some embodiments, R¹ is —N(R)C(O)R. In some embodiments, R¹ is—N(R)C(O)OR. In some embodiments, R¹ is —N(R)C(O)N(R)₂. In someembodiments, R¹ is —N(R)S(O)₂R. In some embodiments, R¹ is—N(R)S(O)₂N(R)₂. In some embodiments, R¹ is —C(O)OH. In someembodiments, R¹ is —C(O)R^(x). In some embodiments, R¹ is—C(O)N(R)S(O)₂R. In some embodiments, R¹ is —C(O)NHS(O)₂R. In someembodiments, R¹ is —C(O)NHS(O)₂Me. In some embodiments, R¹ is —S(O)₂OH.In some embodiments, R¹ is —S(O)R^(y). In some embodiments, R¹ is—S(O)₂R^(y). In some embodiments, R¹ is —S(O)₂N(R)C(O)R. In someembodiments, R¹ is —S(O)₂NHC(O)R. In some embodiments, R¹ is—S(O)₂NHC(O)Me.

In some embodiments, R¹ is R. In some embodiments, R¹ is phenyl. In someembodiments, R¹ is pyridinyl. In some embodiments, R¹ is 2-pyridinyl. Insome embodiments, R¹ is 3-pyridinyl. In some embodiments, R¹ is4-pyridinyl. In some embodiments, R¹ is morpholino.

As defined generally above, R^(x) of formula I, II, III, IV, V, VI, orVII is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R, —N(R)C(O)OR,—N(R)C(O)N(R)₂, or —N(R)S(O)₂R. In some embodiments, R^(x) is —C(O)OR.In some embodiments, R^(x) is —N(R)S(O)₂CF₃. In some embodiments, R^(x)is —N(R)C(O)R. In some embodiments, R^(x) is —NHC(O)R. In someembodiments, R^(x) is —NHC(O)R, wherein R is not hydrogen. In someembodiments, R^(x) is —N(R)C(O)OR. In some embodiments, R^(x) is—NHC(O)OR. In some embodiments, R^(x) is —NHC(O)OR, wherein R is nothydrogen. In some embodiments, R^(x) is —N(R)C(O)N(R)₂. In someembodiments, R^(x) is —NHC(O)N(R)₂. In some embodiments, R^(x) is—NHC(O)N(R)₂, wherein at least one R is not hydrogen. In someembodiments, R^(x) is —N(R)S(O)₂R. In some embodiments, R^(x) is—NHS(O)₂R. In some embodiments, R^(w) is —NHS(O)₂R, wherein R is nothydrogen.

As defined generally above, R^(y) of formula I, II, III, IV, V, VI, orVII is selected from —N(R)C(O)CF₃, —N(R)C(O)R, or —N(R)C(O)N(R)₂. Insome embodiments, R^(y) is —N(R)C(O)CF₃. In some embodiments, R^(y) is—NHC(O)CF₃. In some embodiments, R^(y) is —N(R)C(O)R. In someembodiments, R^(y) is —NHC(O)R. In some embodiments, R^(y) is —NHC(O)R,wherein R is not hydrogen. In some embodiments, R^(y) is —N(R)C(O)N(R)₂.In some embodiments, R^(y) is —NHC(O)N(R)₂. In some embodiments, R^(y)is —NHC(O)N(R)₂, wherein at least one R is not hydrogen.

As defined generally above, each R of formula I, II, III, IV, V, VI, orVII is independently selected from hydrogen or an optionally substitutedgroup selected from C₁₋₁₂ aliphatic or a ring selected from a 3-10membered saturated or partially unsaturated carbocyclic ring, phenyl, a6-10 membered bicyclic saturated, partially unsaturated or aryl ring, a3-8 membered saturated or partially unsaturated heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur,a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclicsaturated or partially unsaturated heterocyclic ring having 1-5heteroatoms independently selected from nitrogen, oxygen or sulfur, oran 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, each R is independently selected from hydrogen or anoptionally substituted group selected from C₁₋₆ aliphatic or a ringselected from a 3-10 membered saturated or partially unsaturatedcarbocyclic ring, phenyl, a 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, R is hydrogen.

In some embodiments, R is an optionally substituted group selected fromC₁₋₁₂ aliphatic or a ring selected from a 3-10 membered saturated orpartially unsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclicsaturated, partially unsaturated or aryl ring, a 3-8 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated orpartially unsaturated heterocyclic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen or sulfur, or an 8-10membered bicyclic heteroaryl ring having 1-5 heteroatoms independentlyselected from nitrogen, oxygen or sulfur. In some embodiments, R is anoptionally substituted group selected from C₁₋₆ aliphatic or a ringselected from a 3-10 membered saturated or partially unsaturatedcarbocyclic ring, phenyl, a 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, R is substituted. In some embodiments, R isunsubstituted.

In some embodiments, R is optionally substituted C₁₋₁₂ aliphatic. Insome embodiments, R is optionally substituted C₁₋₁₀ aliphatic. In someembodiments, R is optionally substituted C₁₋₆ aliphatic. In someembodiments, R is optionally substituted C₁₋₆ alkyl. In someembodiments, R is optionally substituted hexyl, pentyl, butyl, propyl,ethyl or methyl. In some embodiments, R is optionally substituted hexyl.In some embodiments, R is optionally substituted pentyl. In someembodiments, R is optionally substituted butyl. In some embodiments, Ris optionally substituted propyl. In some embodiments, R is optionallysubstituted ethyl. In some embodiments, R is optionally substitutedmethyl. In some embodiments, R is hexyl. In some embodiments, R ispentyl. In some embodiments, R is butyl. In some embodiments, R ispropyl. In some embodiments, R is ethyl. In some embodiments, R ismethyl. In some embodiments, R is isopropyl. In some embodiments, R isn-propyl. In some embodiments, R is tert-butyl. In some embodiments, Ris sec-butyl. In some embodiments, R is n-butyl. In some embodiments, Ris optionally substituted adamantyl. In some embodiments, R is

In some embodiments, R is

In some embodiments, R is an optionally substituted 3-10 memberedsaturated or partially unsaturated carbocyclic ring. In someembodiments, R is an optionally substituted 3-10 membered saturated orpartially unsaturated monocyclic, bicyclic or polycyclic carbocyclicring. In some embodiments, R is an optionally substituted 3-10 memberedsaturated or partially unsaturated monocyclic, bicyclic or tricycliccarbocyclic ring. In some embodiments, R is an optionally substituted3-10 membered saturated or partially unsaturated monocyclic or bicycliccarbocyclic ring. In some embodiments, R is an optionally substituted3-10 membered saturated or partially unsaturated monocyclic carbocyclicring. In some embodiments, R is an optionally substituted 4-10 memberedsaturated or partially unsaturated bicyclic carbocyclic ring. In someembodiments, R is an optionally substituted 4-10 membered saturated orpartially unsaturated polycyclic carbocyclic ring. In some embodiments,R is an optionally substituted 3-10 membered saturated or partiallyunsaturated tricyclic carbocyclic ring. In some embodiments, R is anoptionally substituted 3-membered saturated or partially unsaturatedmonocyclic carbocyclic ring. In some embodiments, R is an optionallysubstituted 4-membered saturated or partially unsaturated monocycliccarbocyclic ring. In some embodiments, R is an optionally substituted5-membered saturated or partially unsaturated monocyclic carbocyclicring. In some embodiments, R is an optionally substituted 6-memberedsaturated or partially unsaturated monocyclic carbocyclic ring. In someembodiments, R is an optionally substituted 6-membered saturated orpartially unsaturated bicyclic carbocyclic ring. In some embodiments, Ris an optionally substituted 7-membered saturated or partiallyunsaturated monocyclic carbocyclic ring. In some embodiments, R is anoptionally substituted 7-membered saturated or partially unsaturatedbicyclic carbocyclic ring. In some embodiments, R is an optionallysubstituted 8-membered saturated or partially unsaturated monocycliccarbocyclic ring. In some embodiments, R is an optionally substituted8-membered saturated or partially unsaturated bicyclic carbocyclic ring.In some embodiments, R is an optionally substituted 9-membered saturatedor partially unsaturated monocyclic carbocyclic ring. In someembodiments, R is an optionally substituted 9-membered saturated orpartially unsaturated bicyclic carbocyclic ring. In some embodiments, Ris an optionally substituted 9-membered saturated or partiallyunsaturated tricyclic carbocyclic ring. In some embodiments, R is

In some embodiments, R is an optionally substituted 10-memberedsaturated or partially unsaturated monocyclic carbocyclic ring. In someembodiments, R is an optionally substituted 10-membered saturated orpartially unsaturated bicyclic carbocyclic ring. In some embodiments, Ris an optionally substituted 10-membered saturated or partiallyunsaturated tricyclic carbocyclic ring.

In some embodiments, R is an optionally substituted 3-8 memberedsaturated monocyclic carbocyclic ring. In some embodiments, R is anoptionally substituted cycloheptyl. In some embodiments, R is anoptionally substituted cyclohexyl. In some embodiments, R is anoptionally substituted cyclopentyl. In some embodiments, R is anoptionally substituted cyclobutyl. In some embodiments, R is anoptionally substituted cyclopropyl.

In some embodiments, R is an optionally substituted 3-8 memberedunsaturated monocyclic carbocyclic ring. In some embodiments, R is anoptionally substituted cycloheptenyl. In some embodiments, R is anoptionally substituted cyclohexenyl. In some embodiments, R is anoptionally substituted cyclopentenyl. In some embodiments, R is anoptionally substituted cyclobutenyl. In some embodiments, R is anoptionally substituted cyclopropyl.

In some embodiments, R is

In some embodiments, R is optionally substituted phenyl. In someembodiments, R is unsubstituted phenyl. In some embodiments, R issubstituted phenyl. In some embodiments, R is 4-bromophenyl. In someembodiments, R is 2-trifluoromethylphenyl. In some embodiments, R is4-trifluoromethylphenyl. In some embodiments, R is 2-cyanophenyl. Insome embodiments, R is 3-cyanophenyl. In some embodiments, R is4-cyanophenyl. In some embodiments, R is 2-nitrophenyl. In someembodiments, R is 3-nitrophenyl. In some embodiments, R is4-nitrophenyl.

In some embodiments, R is a 6-10 membered bicyclic saturated, partiallyunsaturated or aryl ring. In some embodiments, R is a 6-10 memberedbicyclic saturated ring. In some embodiments, R is an 8-10 memberedbicyclic partially unsaturated ring. In some embodiments, R is an 8-10membered bicyclic aryl ring. In some embodiments, R is optionallysubstituted naphthyl. In some embodiments, R is

In some embodiments, R is an optionally substituted 3-8 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen or sulfur. Insome embodiments, R is a substituted 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen or sulfur. In some embodiments, R is anunsubstituted 3-8 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, R is an optionally substituted 3-8 memberedsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen or sulfur. In some embodiments, R is asubstituted 3-8 membered saturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen or sulfur. Insome embodiments, R is an unsubstituted 3-8 membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, R is an optionally substituted 3-membered saturatedheterocyclic ring having one heteroatom selected from nitrogen, oxygenor sulfur. Exemplary R groups include but are not limited to optionallysubstituted aziridinyl, thiiranyl or oxiranyl. In some embodiments, R isa substituted 3-membered saturated heterocyclic ring having oneheteroatom selected from nitrogen, oxygen or sulfur. In someembodiments, R is an unsubstituted saturated 3-membered heterocyclicring having one heteroatom selected from nitrogen, oxygen or sulfur.

In some embodiments, R is an optionally substituted 4-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted azetidinyl, oxetanyl, thietanyl,oxazetidinyl, thiazetidinyl, or diazetidinyl. In some embodiments, R isa substituted 4-membered saturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R is an unsubstituted 4-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R is an optionally substituted 5-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, oxazolidinyl, dioxolanyl, oxathiolanyl,thiazolidinyl, dithiolanyl, imidazolidinyl, isothiazolidinyl,pyrazolidinyl, isoxazolidinyl, or thiazolidinyl. In some embodiments, Ris a substituted 5-membered saturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R is an unsubstituted 5-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R is an optionally substituted 6-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl,dithianyl, dioxanyl, and oxathianyl. In some embodiments, R is asubstituted 6-membered saturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R is an unsubstituted 6-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R is optionally substituted 7-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted azepanyl, oxepanyl, thiepanyl,diazepanyl, oxazepanyl, thiazepanyl, dioxepanyl, oxathiepanyl, ordithiepanyl. In some embodiments, R is a substituted 7-memberedsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R is anunsubstituted 7-membered saturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R is optionally substituted 8-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R is a substituted8-membered saturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R is an unsubstituted 8-membered saturated heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, R is an optionally substituted 3-8 memberedpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In certainembodiments, R is an optionally substituted 5-7 membered partiallyunsaturated ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, R is an optionallysubstituted 5-6 membered partially unsaturated ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R is an optionally substituted 5-memberedpartially unsaturated ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted dihydroimidazolyl, dihydrothiazolyl,dihydrooxazolyl, or oxazolinyl.

In certain embodiments, R is an optionally substituted 6-memberedpartially unsaturated ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl,tetrahydropyrazinyl, dihydrodioxinyl, dihydrooxathiinyl,dihydrooxazinyl, dihydrodithiine, dihydrothiazine, dioxinyl, oxathiinyl,oxazinyl, dithiinyl, or thiazinyl.

In certain embodiments, R is an optionally substituted 7-memberedpartially unsaturated ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted azepinyl, oxepinyl, thiepinyl,diazepinyl, oxazepinyl, thiazepinyl, triazepinyl, oxadiazepinyl,thiadiazepinyl, dihydroazepinyl, dihydrooxepinyl, dihydrothiepinyl,dihydrodiazepinyl, dihydrooxazepinyl, dihydrothiazepinyl,tetrahydroazepinyl, tetrahydrooxepinyl, tetrahydrothiepinyl,tetrahydrodiazepinyl, tetrahydrooxazepinyl or tetrahydrothiazepinyl.

In some embodiments, R is an optionally substituted 8-membered partiallyunsaturated ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, R is an optionally substituted 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R is a substituted 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, R is anunsubstituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R is an optionally substituted 5-memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R is a substituted5-membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur. In some embodiments, R is anunsubstituted 5-membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R is an optionally substituted 6-membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R is a substituted 6-membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R is an unsubstituted 6-memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R is an optionally substituted 5-memberedheteroaryl ring having one heteroatom selected from nitrogen, oxygen, orsulfur. In some embodiments, R is selected from optionally substitutedpyrrolyl, furanyl, or thienyl. In some embodiments, R is optionallysubstituted pyrrolyl. In some embodiments, R is optionally substitutedfuranyl. In some embodiments, R is optionally substituted thienyl.

In some embodiments, R is an optionally substituted 5-memberedheteroaryl ring having two heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, R is an optionallysubstituted 5-membered heteroaryl ring having one nitrogen atom, and anadditional heteroatom selected from sulfur or oxygen. Exemplary R groupsinclude but are not limited to optionally substituted pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl. In someembodiments, R is optionally substituted pyrazolyl. In some embodiments,R is

In some embodiments, R is

In some embodiments, R is an optionally substituted 5-memberedheteroaryl ring having three heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted triazolyl, oxadiazolyl orthiadiazolyl.

In some embodiments, R is an optionally substituted 5-memberedheteroaryl ring having four heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R groups include but are notlimited to optionally substituted tetrazolyl, oxatriazolyl andthiatriazolyl.

In some embodiments, R is a 6-membered heteroaryl ring having 1-4nitrogen atoms. In some embodiments, R is a 6-membered heteroaryl ringhaving 1-3 nitrogen atoms. In other embodiments, R is an optionallysubstituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. Insome embodiments, R is an optionally substituted 6-membered heteroarylring having four nitrogen atoms. In some embodiments, R is an optionallysubstituted 6-membered heteroaryl ring having three nitrogen atoms. Insome embodiments, R is an optionally substituted 6-membered heteroarylring having two nitrogen atoms. In certain embodiments, R is anoptionally substituted 6-membered heteroaryl ring having one nitrogenatom. Exemplary R groups include but are not limited to optionallysubstituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,or tetrazinyl. In some embodiments, R is optionally substitutedpyridinyl. In some embodiments, R is pyridinyl. In some embodiments, Ris

In some embodiments, R is a 7-10 membered bicyclic saturated orpartially unsaturated heterocyclic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R is optionally substituted indolinyl. In some embodiments,R is optionally substituted isoindolinyl. In some embodiments, R isoptionally substituted 1,2,3,4-tetrahydroquinolinyl. In someembodiments, R is optionally substituted1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, R is an optionallysubstituted azabicyclo[3.2.1]octanyl.

In some embodiments, R is an 8-10 membered bicyclic heteroaryl ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, R is an optionally substituted 5,6-fused heteroarylring having 1-5 heteroatoms independently selected from nitrogen, oxygenor sulfur. In some embodiments, R is an optionally substituted 5,6-fusedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R is an optionallysubstituted 5,6-fused heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R is an optionally substituted 5,6-fused heteroaryl ringhaving two heteroatoms independently selected from nitrogen, oxygen orsulfur. In some embodiments, R is optionally substituted1,4-dihydropyrrolo[3,2-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl,4H-thieno[3,2-b]pyrrolyl, furo[3,2-b]furanyl, thieno[3,2-b]furanyl,thieno[3,2-b]thienyl, 1H-pyrrolo[1,2-a]imidazolyl,pyrrolo[2,1-b]oxazolyl or pyrrolo[2,1-b]thiazolyl. In some embodiments,R is an optionally substituted 5,6-fused heteroaryl ring having threeheteroatoms independently selected from nitrogen, oxygen or sulfur. Insome embodiments, R is optionally substituted dihydropyrroloimidazolyl,1H-furoimidazolyl, 1H-thienoimidazolyl, furooxazolyl, furoisoxazolyl,4H-pyrrolooxazolyl, 4H-pyrroloisoxazolyl, thienooxazolyl,thienoisoxazolyl, 4H-pyrrolothiazolyl, furothiazolyl, thienothiazolyl,1H-imidazoimidazolyl, imidazooxazolyl or imidazo[5,1-b]thiazolyl. Insome embodiments, R is an optionally substituted 5,6-fused heteroarylring having four heteroatoms independently selected from nitrogen,oxygen or sulfur. In some embodiments, R is an optionally substituted5,6-fused heteroaryl ring having five heteroatoms independently selectedfrom nitrogen, oxygen or sulfur.

In some embodiments, R is an optionally substituted 5,6-fused heteroarylring having 1-5 heteroatoms independently selected from nitrogen, oxygenor sulfur. In other embodiments, R is an optionally substituted5,6-fused heteroaryl ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur. In certain embodiments, R is anoptionally substituted 5,6-fused heteroaryl ring having one heteroatomindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R is optionally substituted indolyl. In some embodiments, Ris optionally substituted benzofuranyl. In some embodiments, R isoptionally substituted benzo[b]thienyl. In certain embodiments, R is anoptionally substituted 5,6-fused heteroaryl ring having two heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R is optionally substituted azaindolyl. In someembodiments, R is optionally substituted benzimidazolyl. In someembodiments, R is optionally substituted benzothiazolyl. In someembodiments, R is optionally substituted benzoxazolyl. In someembodiments, R is an optionally substituted indazolyl. In certainembodiments, R is an optionally substituted 5,6-fused heteroaryl ringhaving three heteroatoms independently selected from nitrogen, oxygen orsulfur. In some embodiments, R is optionally substitutedoxazolopyridiyl, thiazolopyridinyl or imidazopyridinyl. In certainembodiments, R is an optionally substituted 5,6-fused heteroaryl ringhaving four heteroatoms independently selected from nitrogen, oxygen orsulfur. In some embodiments, R is optionally substituted purinyl,oxazolopyrimidinyl, thiazolopyrimidinyl, oxazolopyrazinyl,thiazolopyrazinyl, imidazopyrazinyl, oxazolopyridazinyl,thiazolopyridazinyl or imidazopyridazinyl. In certain embodiments, R isan optionally substituted 5,6-fused heteroaryl ring having fiveheteroatoms independently selected from nitrogen, oxygen or sulfur. Insome embodiments, R is

In certain embodiments, R is an optionally substituted 6,6-fusedheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R is an optionallysubstituted 6,6-fused heteroaryl ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In otherembodiments, R is an optionally substituted 6,6-fused heteroaryl ringhaving one heteroatom selected from nitrogen, oxygen or sulfur. In someembodiments, R is optionally substituted quinolinyl. In someembodiments, R is optionally substituted isoquinolinyl. In someembodiments, R is an optionally substituted 6,6-fused heteroaryl ringhaving two heteroatoms independently selected from nitrogen, oxygen orsulfur. In some embodiments, R is optionally substituted quinazolinyl,phthalazinyl, quinoxalinyl or naphthyridinyl. In some embodiments, R isan optionally substituted 6,6-fused heteroaryl ring having threeheteroatoms independently selected from nitrogen, oxygen or sulfur. Insome embodiments, R is optionally substituted pyridopyrimidinyl,pyridopyridazinyl, pyridopyrazinyl, or benzotriazinyl. In someembodiments, R is an optionally substituted 6,6-fused heteroaryl ringhaving four heteroatoms independently selected from nitrogen, oxygen orsulfur. In some embodiments, R is optionally substitutedpyridotriazinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl,pyridazinopyridazinyl, pyrimidopyridazinyl or pyrimidopyrimidinyl. Insome embodiments, R is an optionally substituted 6,6-fused heteroarylring having five heteroatoms independently selected from nitrogen,oxygen or sulfur.

As defined generally above, R² of formula I or II is —C(O)-L³-R^(z),—C(O)N(R)-L³-R^(z), —C(O)N(R)—C(R)₂-L³-R^(z), —C(O)O-L³-R^(z) or—C(O)S-L³-R^(z).

In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein the R group attached to the nitrogenatom and R¹ are optionally taken together with their intervening atomsto form an optionally substituted 4-8 membered saturated, partiallyunsaturated or aryl ring having 2-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z), wherein the R group attached to the nitrogen atomand R¹ are optionally taken together with their intervening atoms toform an optionally substituted 4-8 membered saturated, partiallyunsaturated or aryl ring having 2-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)—C(R)₂-L³-R^(z), wherein the R group attached to the nitrogenatom and R¹ are optionally taken together with their intervening atomsto form an optionally substituted 4-8 membered saturated, partiallyunsaturated or aryl ring having 2-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)-L³-R^(z). In some embodiments, R² is—C(O)N(R)-L³-R^(z). In some embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z).In some embodiments, R² is —C(O)O-L³-R^(z). In some embodiments, R² is—C(O)S-L³-R^(z).

As generally defined above, L³ of formula I or II is selected from acovalent bond or an optionally substituted bivalent straight or branchedC₁₋₈ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy-, —O—, —S—, —N(R)—,—N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or—S(O)₂N(R)—. In some embodiments, L³ is selected from a covalent bond oran optionally substituted bivalent straight or branched C₁₋₈ hydrocarbonchain wherein one or more methylene units are optionally andindependently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —C(O)—,—C(O)N(R)—, or —S(O)—. In some embodiments, L³ is selected from acovalent bond or an optionally substituted bivalent straight or branchedC₁₋₈ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy-, —O—, —N(R)—,—N(R)C(O)—, —C(O)—, or —C(O)N(R)—. L³ is selected from a covalent bondor an optionally substituted bivalent straight or branched C₁₋₈hydrocarbon chain wherein one or more methylene units are optionally andindependently replaced with -Cy- or —O—.

In some embodiments, L³ is a covalent bond. In some embodiments, L³ isan optionally substituted bivalent straight or branched C₁₋₈ hydrocarbonchain wherein one or more methylene units are optionally andindependently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—,—N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. Insome embodiments, L³ is an optionally substituted methylene group or-Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—,—S(O)—, —S(O)₂—, or —S(O)₂N(R)—. In some embodiments, L³ is anoptionally substituted bivalent straight or branched C₂ hydrocarbonchain wherein one or more methylene units are optionally andindependently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—,—N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. Insome embodiments, L³ is an optionally substituted bivalent straight orbranched C₃ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy-, —O—, —S—, —N(R)—,—N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or—S(O)₂N(R)—. In some embodiments, L³ is an optionally substitutedbivalent straight or branched C₄ hydrocarbon chain wherein one or moremethylene units are optionally and independently replaced with -Cy-,—O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—,—S(O)₂—, or —S(O)₂N(R)—. In some embodiments, L³ is an optionallysubstituted bivalent straight or branched C₅ hydrocarbon chain whereinone or more methylene units are optionally and independently replacedwith -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—,—C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. In some embodiments, L³ isan optionally substituted bivalent straight or branched C₆ hydrocarbonchain wherein one or more methylene units are optionally andindependently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—,—N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. Insome embodiments, L³ is an optionally substituted bivalent straight orbranched C₇ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy-, —O—, —S—, —N(R)—,—N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or—S(O)₂N(R)—. In some embodiments, L³ is an optionally substitutedbivalent straight or branched C₈ hydrocarbon chain wherein one or moremethylene units are optionally and independently replaced with -Cy-,—O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—,—S(O)₂—, or —S(O)₂N(R)—.

In some embodiments, L³ is an optionally substituted bivalent straightor branched C₁₋₈ hydrocarbon chain wherein one or more methylene unitsare independently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—,—N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. Insome embodiments, L³ is an optionally substituted bivalent straight orbranched C₁₋₈ hydrocarbon chain wherein one or more methylene units areindependently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —C(O)—,—C(O)N(R)—, or —S(O)—. In some embodiments, L³ is an optionallysubstituted bivalent straight or branched C₁₋₈ hydrocarbon chain whereinone or more methylene units are independently replaced with -Cy-, —O—,—N(R)—, —N(R)C(O)—, —C(O)—, or —C(O)N(R)—. In some embodiments, L³ is anoptionally substituted bivalent straight or branched C₁₋₈ hydrocarbonchain wherein one or more methylene units are independently replacedwith -Cy- or —O—.

In some embodiments, L³ is an optionally substituted bivalent straightor branched C₁₋₈ hydrocarbon chain. In some embodiments, L³ is abivalent straight or branched C₁₋₈ hydrocarbon chain. In someembodiments, L³ is a bivalent straight C₁₋₈ hydrocarbon chain.

In some embodiments, one or more methylene units of L³ are optionallyand independently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—,—C(O)—, —C(O)N(R)—, or —S(O)—. In some embodiments, R² is—C(O)-L³-R^(z), —C(O)N(R)-L³-R^(z), —C(O)N(R)—C(R)₂-L³-R^(z),—C(O)O-L³-R^(z) or —C(O)S-L³-R^(z), wherein the methylene unit of L³that is directly bonded to said —C(O)—, —C(O)N(R)—, —C(O)N(R)—C(R)₂—,—C(O)O— or —C(O)S— moiety is optionally and independently replaced by-Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —C(O)—, —C(O)N(R)—, or —S(O)—. Insome embodiments, one or more methylene units of L³ are optionally andindependently replaced with -Cy-, —O—, —N(R)—, —N(R)C(O)—, —C(O)—, or—C(O)N(R)—. In some embodiments, R² is —C(O)-L³-R^(z),—C(O)N(R)-L³-R^(z), —C(O)N(R)—C(R)₂-L³-R^(z), —C(O)O-L³-R^(z) or—C(O)S-L³-R^(z), wherein the methylene unit of L³ that is directlybonded to said —C(O)—, —C(O)N(R)—, —C(O)N(R)—C(R)₂—, —C(O)O— or —C(O)S—moiety is optionally and independently replaced by -Cy-, —O—, —N(R)—,—N(R)C(O)—, —C(O)—, or —C(O)N(R)—. In some embodiments, one or moremethylene units of L³ are optionally and independently replaced with-Cy- or —O—. In some embodiments, R² is —C(O)-L³-R^(z),—C(O)N(R)-L³-R^(z), —C(O)N(R)—C(R)₂-L³-R^(z), —C(O)O-L³-R^(z) or—C(O)S-L³-R^(z), wherein the methylene unit of L³ that is directlybonded to said —C(O)—, —C(O)N(R)—, —C(O)N(R)—C(R)₂—, —C(O)O— or —C(O)S—moiety is optionally and independently replaced by -Cy- or —O—.

In some embodiments, one or more methylene units are independentlyreplaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—,—C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. In some embodiments, one ormore methylene units are replaced with -Cy-. In some embodiments, one ormore methylene units are replaced with —O—. In some embodiments, one ormore methylene units are replaced with —S—. In some embodiments, one ormore methylene units are replaced with —N(R)—. In some embodiments, oneor more methylene units are replaced with —N(R)C(O)—. In someembodiments, one or more methylene units are replaced with —N(R)S(O)₂—.In some embodiments, one or more methylene units are replaced with—C(O)—. In some embodiments, one or more methylene units are replacedwith —C(O)N(R)—. In some embodiments, one or more methylene units arereplaced with —S(O)—. In some embodiments, one or more methylene unitsare replaced with —S(O)₂—. In some embodiments, one or more methyleneunits are replaced with —S(O)₂N(R)—.

In some embodiments, the methylene unit of L³ that is directly bonded toR^(z) is optionally replaced with -Cy-. In some embodiments, themethylene unit of L³ that is directly bonded to R^(z) is replaced with-Cy-. In some embodiments, the methylene unit of L³ that is directlybonded to R^(z) is replaced with an optionally substituted phenylene. Insome embodiments, the methylene unit of L³ that is directly bonded toR^(z) is replaced with an optionally substituted 5-6 memberedheteroarylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, L³ is —NRS(O)₂(CH₂)₂N(R)C(O)—.

As generally defined above, R^(z) of formula I or II is hydrogen, R,—OR, —SR, —S(O)R, —S(O)₂R, —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂, —C(O)R,—N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —N(R)S(O)₂N(R)₂,—C(O)OH, —C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

In some embodiments, R^(z) is —OR, —SR, —S(O)R, —S(O)₂R, —S(O)₂N(R)₂,—N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x), —S(O)₂OH, or—S(O)₂R^(y), or is selected from:

In some embodiments, R^(z) is —S(O)R, —S(O)₂R, —S(O)₂N(R)₂, —N(R)₂,—C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x), —S(O)₂OH, or—S(O)₂R^(y), or is selected from:

In some embodiments, R^(z) is —S(O)₂N(R)₂, —C(O)N(R)₂, —C(O)OH,—C(O)R^(x), —S(O)₂H, or —S(O)₂R^(y), or is selected from:

In some embodiments, R^(z) is —S(O)₂N(R)₂, —C(O)N(R)₂, —C(O)OH,—C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y). In some embodiments, R^(z) is—COOH, —C(O)N(R)SO₂R or —SO₂N(R)C(O)R. In some embodiments, R^(z) is—COOH, —C(O)NHSO₂R or —SO₂NHC(O)R.

In some embodiments, R^(z) is hydrogen. In some embodiments, R^(z) isnot hydrogen.

In some embodiments, R^(z) is R. In some embodiments, R^(z) is R,wherein R is not hydrogen.

In some embodiments, R^(z) is —OR. In some embodiments, R^(z)—SR. Insome embodiments, R^(z) is —S(O)R. In some embodiments, R^(z) is—S(O)₂R. In some embodiments, R^(z) is —S(O)₂N(R)₂. In some embodiments,R^(z) is —N(R)₂. In some embodiments, R^(z) is —C(O)N(R)₂. In someembodiments, R^(z) is —C(O)R. In some embodiments, R^(z) is —N(R)C(O)R.In some embodiments, R^(z) is —N(R)C(O)OR. In some embodiments, R^(z) is—N(R)C(O)N(R)₂. In some embodiments, R^(z) is —N(R)S(O)₂R. In someembodiments, R^(z) is —N(R)S(O)₂N(R)₂.

In some embodiments, R^(z) is —C(O)OH.

In some embodiments, R^(z) is —C(O)R^(x). In some embodiments, R^(z) is—C(O)N(R)S(O)₂R. In some embodiments, R^(z) is —C(O)NHS(O)₂R. In someembodiments, R^(z) is —C(O)N(R)S(O)₂R, wherein R is not hydrogen. Insome embodiments, R^(z) is —C(O)NHS(O)₂R, wherein R is not hydrogen. Insome embodiments, R^(z) is —C(O)N(R)S(O)₂R, wherein R is optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R^(z) is —C(O)NHS(O)₂R,wherein R is optionally substituted C₁₋₆ aliphatic. In some embodiments,R^(z) is —C(O)N(R)S(O)₂Me. In some embodiments, R^(z) is —C(O)NHS(O)₂Me.In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is —S(O)₂OH.

In some embodiments, R^(z) is —S(O)₂R^(y). In some embodiments, R^(z) is—S(O)₂N(R)C(O)R. In some embodiments, R^(z) is —S(O)₂NHC(O)R. In someembodiments, R^(z) is —S(O)₂N(R)C(O)R, wherein R is not hydrogen. Insome embodiments, R^(z) is —S(O)₂NHC(O)R, wherein R is not hydrogen. Insome embodiments, R^(z) is —S(O)₂N(R)C(O)R, wherein R is optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R^(z) is —S(O)₂NHC(O)R,wherein R is optionally substituted C₁₋₆ aliphatic. In some embodiments,R^(z) is —S(O)₂N(R)C(O)Me. In some embodiments, R^(z) is —S(O)₂NHC(O)Me.In some embodiments, R^(z) is —S(O)₂NHC(O)Me. In some embodiments, R^(z)is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is selected from:

As defined generally above, R^(2′) of formula V or VII is—C(O)-L⁴-R^(w), —C(O)N(R)-L⁴-R^(w), —C(O)N(R)—C(R)₂-L⁴-R^(w),—C(O)O-L⁴-R^(w) or —C(O)S-L⁴-R^(w).

In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R¹ are optionally taken together with their intervening atomsto form an optionally substituted 4-8 membered saturated, partiallyunsaturated or aryl ring having 2-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w), wherein the R group attached to the nitrogen atomand R¹ are optionally taken together with their intervening atoms toform an optionally substituted 4-8 membered saturated, partiallyunsaturated or aryl ring having 2-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R¹ are optionally taken together with their intervening atomsto form an optionally substituted 4-8 membered saturated, partiallyunsaturated or aryl ring having 2-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)-L⁴-R^(w). In some embodiments,R^(2′) is —C(O)N(R)-L⁴-R^(w). In some embodiments, R^(2′) is—C(O)N(R)—C(R)₂-L⁴-R^(w). In some embodiments, R^(2′) is—C(O)O-L⁴-R^(w). In some embodiments, R^(2′) is —C(O)S-L⁴-R^(w).

As defined generally above, L⁴ of formula III, IV, V, VI, or VII isindependently selected from a covalent bond or an optionally substitutedbivalent straight or branched C₁₋₈ hydrocarbon chain wherein one or moremethylene units are optionally and independently replaced with -Cy′-,—O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—,—S(O)₂—, or —S(O)₂N(R)—.

In some embodiments, L⁴ is selected from a covalent bond or anoptionally substituted bivalent straight or branched C₁₋₈ hydrocarbonchain wherein one or more methylene units are optionally andindependently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —C(O)—,—C(O)N(R)—, or —S(O)—. In some embodiments, L⁴ is selected from acovalent bond or an optionally substituted bivalent straight or branchedC₁₋₈ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy′-, —O—, —N(R)—,—N(R)C(O)—, —C(O)—, or —C(O)N(R)—. L⁴ is selected from a covalent bondor an optionally substituted bivalent straight or branched C₁₋₈hydrocarbon chain wherein one or more methylene units are optionally andindependently replaced with -Cy′- or —O—.

In some embodiments, L⁴ is a covalent bond. In some embodiments, L⁴ isan optionally substituted bivalent straight or branched C₁₋₈ hydrocarbonchain wherein one or more methylene units are optionally andindependently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—,—N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. Insome embodiments, L⁴ is an optionally substituted methylene group or-Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—,—S(O)—, —S(O)₂—, or —S(O)₂N(R)—. In some embodiments, L⁴ is anoptionally substituted bivalent straight or branched C₂ hydrocarbonchain wherein one or more methylene units are optionally andindependently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—,—N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. Insome embodiments, L⁴ is an optionally substituted bivalent straight orbranched C₃ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy′-, —O—, —S—, —N(R)—,—N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or—S(O)₂N(R)—. In some embodiments, L⁴ is an optionally substitutedbivalent straight or branched C₄ hydrocarbon chain wherein one or moremethylene units are optionally and independently replaced with -Cy′-,—O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—,—S(O)₂—, or —S(O)₂N(R)—. In some embodiments, L⁴ is an optionallysubstituted bivalent straight or branched C₅ hydrocarbon chain whereinone or more methylene units are optionally and independently replacedwith -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—,—C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. In some embodiments, L⁴ isan optionally substituted bivalent straight or branched C₆ hydrocarbonchain wherein one or more methylene units are optionally andindependently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—,—N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. Insome embodiments, L⁴ is an optionally substituted bivalent straight orbranched C₇ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy′-, —O—, —S—, —N(R)—,—N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or—S(O)₂N(R)—. In some embodiments, L⁴ is an optionally substitutedbivalent straight or branched C₁₋₈ hydrocarbon chain wherein one or moremethylene units are optionally and independently replaced with -Cy′-,—O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—,—S(O)₂—, or —S(O)₂N(R)—.

In some embodiments, L⁴ is an optionally substituted bivalent straightor branched C₁₋₈ hydrocarbon chain wherein one or more methylene unitsare independently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—,—N(R)S(O)₂—, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. Insome embodiments, L⁴ is an optionally substituted bivalent straight orbranched C₁₋₈ hydrocarbon chain wherein one or more methylene units areindependently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —C(O)—,—C(O)N(R)—, or —S(O)—. In some embodiments, L⁴ is an optionallysubstituted bivalent straight or branched C₁₋₈ hydrocarbon chain whereinone or more methylene units are independently replaced with -Cy′-, —O—,—N(R)—, —N(R)C(O)—, —C(O)—, or —C(O)N(R)—. In some embodiments, L⁴ is anoptionally substituted bivalent straight or branched C₁₋₈ hydrocarbonchain wherein one or more methylene units are independently replacedwith -Cy′- or —O—.

In some embodiments, L⁴ is an optionally substituted bivalent straightor branched C₁₋₈ hydrocarbon chain. In some embodiments, L⁴ is abivalent straight or branched C₁₋₈ hydrocarbon chain. In someembodiments, L⁴ is a bivalent straight C₁₋₈ hydrocarbon chain.

In some embodiments, one or more methylene units of L⁴ are optionallyand independently replaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—,—C(O)—, —C(O)N(R)—, or —S(O)—. In some embodiments, R^(2′) is—C(O)-L⁴-R^(w), —C(O)N(R)-L⁴-R^(w), —C(O)N(R)—C(R)₂-L⁴-R^(w),—C(O)O-L⁴-R^(w) or —C(O)S-L⁴-R^(w), wherein the methylene unit of L⁴that is directly bonded to said —C(O)—, —C(O)N(R)—, —C(O)N(R)—C(R)₂—,—C(O)O— or —C(O)S— moiety is optionally and independently replaced by-Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —C(O)—, —C(O)N(R)—, or —S(O)—. Insome embodiments, one or more methylene units of L⁴ are optionally andindependently replaced with -Cy′-, —O—, —N(R)—, —N(R)C(O)—, —C(O)—, or—C(O)N(R)—. In some embodiments, R^(2′) is —C(O)-L⁴-R^(w),—C(O)N(R)-L⁴-R^(w), —C(O)N(R)—C(R)₂-L⁴-R, —C(O)O-L⁴-R^(w) or—C(O)S-L⁴-R^(w), wherein the methylene unit of L⁴ that is directlybonded to said —C(O)—, —C(O)N(R)—, —C(O)N(R)—C(R)₂—, —C(O)O— or —C(O)S—moiety is optionally and independently replaced by -Cy′-, —O—, —N(R)—,—N(R)C(O)—, —C(O)—, or —C(O)N(R)—. In some embodiments, one or moremethylene units of L⁴ are optionally and independently replaced with-Cy′- or —O—. In some embodiments, R^(2′) is —C(O)-L⁴-R^(w),—C(O)N(R)-L⁴-R^(w), —C(O)N(R)—C(R)₂-L⁴⁻R^(w), —C(O)O-L⁴-R^(w) or—C(O)S-L⁴-R^(w), wherein the methylene unit of L⁴ that is directlybonded to said —C(O)—, —C(O)N(R)—, —C(O)N(R)—C(R)₂—, —C(O)O— or —C(O)S—moiety is optionally and independently replaced by -Cy′- or —O—.

In some embodiments, one or more methylene units are independentlyreplaced with -Cy′-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O)₂—, —C(O)—,—C(O)N(R)—, —S(O)—, —S(O)₂—, or —S(O)₂N(R)—. In some embodiments, one ormore methylene units are replaced with -Cy′-. In some embodiments, oneor more methylene units are replaced with —O—. In some embodiments, oneor more methylene units are replaced with —S—. In some embodiments, oneor more methylene units are replaced with —N(R)—. In some embodiments,one or more methylene units are replaced with —N(R)C(O)—. In someembodiments, one or more methylene units are replaced with —N(R)S(O)₂—.In some embodiments, one or more methylene units are replaced with—C(O)—. In some embodiments, one or more methylene units are replacedwith —C(O)N(R)—. In some embodiments, one or more methylene units arereplaced with —S(O)—. In some embodiments, one or more methylene unitsare replaced with —S(O)₂—. In some embodiments, one or more methyleneunits are replaced with —S(O)₂N(R)—.

In some embodiments, the methylene unit of L⁴ that is directly bonded toR^(w) is optionally replaced with -Cy′-. In some embodiments, themethylene unit of L⁴ that is directly bonded to R^(w) is replaced with-Cy′-. In some embodiments, the methylene unit of L⁴ that is directlybonded to R^(w) is replaced with an optionally substituted phenylene. Insome embodiments, the methylene unit of L⁴ that is directly bonded toR^(w) is replaced with an optionally substituted 5-6 memberedheteroarylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, the methylene unit ofL⁴ that is directly bonded to R^(w) is replaced with an optionallysubstituted 3-8 membered saturated or partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, the methylene unit ofL⁴ that is directly bonded to R^(w) is replaced with an optionallysubstituted 8-10 membered bicyclic arylene or heteroarylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, the methylene unit of L⁴ that is directly bonded toR^(w) is replaced with an optionally substituted 8-10 membered saturatedor partially unsaturated heterocyclylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, L⁴ is —NRS(O)₂(CH₂)₂N(R)C(O)—.

As defined generally above, -Cy′- of formula III, IV, V, VI, or VII isan optionally substituted bivalent ring independently selected fromphenylene, 3-8 membered saturated or partially unsaturatedcarbocyclylene, 5-6 membered heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 3-8 memberedsaturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, an8-10 membered bicyclic arylene or heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered saturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy′- is optionally substituted phenylene. In someembodiments, -Cy′- is substituted phenylene. In some embodiments, -Cy′-is unsubstituted phenylene. In some embodiments, -Cy′- is optionallysubstituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is optionally substituted bivalent 3-8membered saturated or partially unsaturated carbocyclylene. In certainembodiments, -Cy′- is optionally substituted bivalent 3-8 memberedsaturated carbocyclylene. In certain embodiments, -Cy′- is optionallysubstituted bivalent 3-6 membered saturated carbocyclylene. In certainembodiments, -Cy′- is optionally substituted bivalent 3-memberedsaturated carbocyclylene. In certain embodiments, -Cy′- is optionallysubstituted bivalent 4-membered saturated carbocyclylene. In certainembodiments, -Cy′- is optionally substituted bivalent 5-memberedsaturated carbocyclylene. In some embodiments -Cy′- is optionallysubstituted

In some embodiments -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted bivalent6-membered saturated carbocyclylene. In some embodiments -Cy′- isoptionally substituted

In some embodiments -Cy′- is optionally substituted

In some embodiments -Cy′- is optionally substituted

In some embodiments -Cy′- is optionally substituted

In some embodiments -Cy′- is optionally substitute

In some embodiments -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted bivalent 5-6membered heteroarylene having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, -Cy′- isoptionally substituted bivalent 5-membered heteroarylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy′- is optionally substituted bivalent 5-memberedheteroarylene having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, -Cy′- is optionallysubstituted bivalent 5-membered heteroarylene having one heteroatomindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is optionally substitute

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted bivalent6-membered heteroarylene having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, -Cy′- isoptionally substituted bivalent 6-membered heteroarylene having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is

In some embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is optionally substituted bivalent 3-8membered saturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy′- is optionally substituted bivalent 3-8membered saturated heterocyclylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In certain embodiments, -Cy′-is optionally substituted bivalent 3-8 membered saturatedheterocyclylene having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, -Cy′- is optionallysubstituted bivalent 5-6 membered saturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy′- is optionally substituted bivalent 5-6membered saturated heterocyclylene having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In certain embodiments, -Cy′-is optionally substituted bivalent 5-membered saturated heterocyclylenehaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In certain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted bivalent6-membered saturated heterocyclylene having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted

In some embodiments, -Cy′- is an optionally substituted bivalent 8-10membered bicyclic arylene or heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, -Cy′- is an optionally substituted bivalent 8-10 memberedbicyclic arylene or heteroarylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In certain embodiments, -Cy′-is an optionally substituted bivalent 8 membered bicyclic arylene orheteroarylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, -Cy′- is anoptionally substituted bivalent 9 membered bicyclic arylene orheteroarylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, -Cy′- is anoptionally substituted

In certain embodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is an optionally substituted.

In certain embodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is an optionally substitute

In certain embodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is an optionally substituted. In certainembodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is

In certain embodiments, -Cy′- is an optionally substituted bivalent 10membered bicyclic arylene or heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is an optionally substituted.

In certain embodiments, -Cy′- is an optionally substituted

In certain embodiments, -Cy′- is an optionally substituted

In some embodiments, -Cy′- is optionally substituted bivalent 8-10membered saturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy′- is optionally substituted bivalent 9 memberedsaturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted

In certain embodiments, -Cy′- is optionally substituted bivalent 10membered saturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, -Cy′- is optionally substituted

As generally defined above, R^(w) of formula III, IV, V, VI, or VII ishydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R, —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂,—C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,—N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR, —C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y),or is selected from:

In some embodiments, R^(w) is —OR, —SR, —S(O)R, —S(O)₂R, —S(O)₂N(R)₂,—N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR, —C(O)R^(x), —S(O)₂OH, or—S(O)₂R^(y), or is selected from:

In some embodiments, R^(w) is —S(O)R, —S(O)₂R, —S(O)₂N(R)₂, —N(R)₂,—C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR, —C(O)R^(x), —S(O)₂OH, or—S(O)₂R^(y), or is selected from:

In some embodiments, R^(w) is —S(O)₂N(R)₂, —C(O)N(R)₂, —C(O)OH, —C(O)OR,—C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y), or is selected from:

In some embodiments, R^(w) is —S(O)₂N(R)₂, —C(O)N(R)₂, —C(O)OH, —C(O)OR,—C(O)R^(x), —S(O)₂OH, or —S(O)₂R^(y). In some embodiments, R^(w) is—COOH, —C(O)OR, —C(O)N(R)SO₂R or —SO₂N(R)C(O)R. In some embodiments,R^(w) is —COOH, —C(O)OR, —C(O)NHSO₂R or —SO₂NHC(O)R.

In some embodiments, R^(w) is hydrogen. In some embodiments, R^(w) isnot hydrogen.

In some embodiments, R^(w) is R. In some embodiments, R^(w) is R,wherein R is not hydrogen.

In some embodiments, R^(w) is —OR. In some embodiments, R^(w)—SR. Insome embodiments, R^(w) is —S(O)R. In some embodiments, R^(w) is—S(O)₂R. In some embodiments, R^(w) is —S(O)₂N(R)₂. In some embodiments,R^(w) is —N(R)₂. In some embodiments, R^(w) is —C(O)N(R)₂. In someembodiments, R^(w) is —C(O)R. In some embodiments, R^(w) is —N(R)C(O)R.In some embodiments, R^(w) is —N(R)C(O)OR. In some embodiments, R^(w) is—N(R)C(O)N(R)₂. In some embodiments, R^(w) is —N(R)S(O)₂R. In someembodiments, R^(w) is —N(R)S(O)₂N(R)₂.

In some embodiments, R^(w) is —C(O)OH. In some embodiments, R^(w) is—C(O)OR. In some embodiments, R^(w) is —C(O)OR, wherein R is C₁₋₆aliphatic. In some embodiments, R^(w) is —C(O)OR, wherein R is methyl.In some embodiments, R^(w) is —C(O)OR, wherein R is ethyl.

In some embodiments, R^(w) is —C(O)R^(x). In some embodiments, R^(w) is—C(O)N(R)S(O)₂R. In some embodiments, R^(w) is —C(O)NHS(O)₂R. In someembodiments, R′ is —C(O)N(R)S(O)₂R, wherein R is not hydrogen. In someembodiments, R^(w) is —C(O)NHS(O)₂R, wherein R is not hydrogen. In someembodiments, R^(w) is —C(O)N(R)S(O)₂R, wherein R is optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R^(w) is —C(O)NHS(O)₂R,wherein R is optionally substituted C₁₋₆ aliphatic. In some embodiments,R^(w) is —C(O)N(R)S(O)₂Me. In some embodiments, R^(w) is —C(O)NHS(O)₂Me.In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is —S(O)₂OH.

In some embodiments, R^(w) is —S(O)₂R^(y). In some embodiments, R^(w) is—S(O)₂N(R)C(O)R. In some embodiments, R^(w) is —S(O)₂NHC(O)R. In someembodiments, R^(w) is —S(O)₂N(R)C(O)R, wherein R is not hydrogen. Insome embodiments, R^(w) is —S(O)₂NHC(O)R, wherein R is not hydrogen. Insome embodiments, R^(w) is —S(O)₂N(R)C(O)R, wherein R is optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R^(w) is —S(O)₂NHC(O)R,wherein R is optionally substituted C₁₋₆ aliphatic. In some embodiments,R^(w) is —S(O)₂N(R)C(O)Me. In some embodiments, R^(w) is —S(O)₂NHC(O)Me.In some embodiments, R^(w) is —S(O)₂NHC(O)Me. In some embodiments, R^(w)is

In some embodiments, R^(w) is

In some embodiments, R^(w) is

In some embodiments, R^(w) is selected from:

As defined generally above, L² of formula I or II is an optionallysubstituted bivalent straight or branched C₃₋₆ hydrocarbon chain whereinone or two methylene units of L² are optionally and independentlyreplaced with —O—, —S—, or —N(R′)—, and wherein two substituents of L²are optionally taken together to form an optionally substituted bivalentring selected from 3-8 membered saturated or partially unsaturatedcarbocyclylene or 3-8 membered saturated or partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, L² is an optionallysubstituted bivalent straight or branched C₃₋₆ hydrocarbon chain whereinone or two methylene units of L² are optionally and independentlyreplaced with —O—, —S—, or —N(R′)—. In some embodiments, twosubstituents of L² are optionally taken together to form an optionallysubstituted bivalent ring selected from 3-8 membered saturated orpartially unsaturated carbocyclylene or 3-8 membered saturated orpartially unsaturated heterocyclylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, two substituents of L² are optionally taken together toform optionally substituted bivalent 3-8 membered saturated or partiallyunsaturated carbocyclylene. In some embodiments, two substituents of L²are optionally taken together to form optionally substituted bivalent3-8 membered saturated or partially unsaturated heterocyclylene having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, L² is a substituted bivalent C₃₋₆ hydrocarbon chainwherein one or two methylene units of L² are optionally andindependently replaced with —O—, —S—, or —N(R′)—. In some embodiments,L² is an unsubstituted bivalent C₃₋₆ hydrocarbon chain wherein one ortwo methylene units of L² are optionally and independently replaced with—O—, —S—, or —N(R′)—. In some embodiments, L² is a substituted bivalentC₃₋₆ hydrocarbon. In some embodiments, L² is an unsubstituted bivalentC₃₋₆ hydrocarbon. In some embodiments, L² is an optionally substitutedbivalent C₄₋₆ hydrocarbon chain wherein one or two methylene units of L²are optionally and independently replaced with —O—, —S—, or —N(R′)—. Insome embodiments, L² is a substituted bivalent C₄₋₆ hydrocarbon chainwherein one or two methylene units of L² are optionally andindependently replaced with —O—, —S—, or —N(R′)—. In some embodiments,L² is an unsubstituted bivalent C₄₋₆ hydrocarbon chain wherein one ortwo methylene units of L² are optionally and independently replaced with—O—, —S—, or —N(R′)—. In some embodiments, L² is a substituted bivalentC₄₋₆ hydrocarbon. In some embodiments, L² is an unsubstituted bivalentC₄₋₆ hydrocarbon. In some embodiments, L² is an optionally substitutedbivalent C₅₋₆ hydrocarbon chain wherein one or two methylene units of L²are optionally and independently replaced with —O—, —S—, or —N(R′)—. Insome embodiments, L² is a substituted bivalent C₅₋₆ hydrocarbon chainwherein one or two methylene units of L² are optionally andindependently replaced with —O—, —S—, or —N(R′)—. In some embodiments,L² is an unsubstituted bivalent C₅₋₆ hydrocarbon chain wherein one ortwo methylene units of L² are optionally and independently replaced with—O—, —S—, or —N(R′)—. In some embodiments, L² is a substituted bivalentC₅₋₆ hydrocarbon. In some embodiments, L² is an unsubstituted bivalentC₅₋₆ hydrocarbon.

In some embodiments, L² is an optionally substituted bivalent C₃hydrocarbon chain wherein one or two methylene units of L² areoptionally and independently replaced with —O—, —S—, or —N(R′)—. In someembodiments, L² is a substituted bivalent C₃ hydrocarbon chain whereinone or two methylene units of L² are optionally and independentlyreplaced with —O—, —S—, or —N(R′)—. In some embodiments, L² is anunsubstituted bivalent C₃ hydrocarbon chain wherein one or two methyleneunits of L² are optionally and independently replaced with —O—, —S—, or—N(R′)—. In some embodiments, L² is a substituted bivalent C₃hydrocarbon chain. In some embodiments, L² is an unsubstituted bivalentC₃ hydrocarbon chain.

In some embodiments, L² is an optionally substituted bivalent C₄hydrocarbon chain wherein one or two methylene units of L² areoptionally and independently replaced with —O—, —S—, or —N(R′)—. In someembodiments, L² is a substituted bivalent C₄ hydrocarbon chain whereinone or two methylene units of L² are optionally and independentlyreplaced with —O—, —S—, or —N(R′)—. In some embodiments, L² is anunsubstituted bivalent C₄ hydrocarbon chain wherein one or two methyleneunits of L² are optionally and independently replaced with —O—, —S—, or—N(R′)—. In some embodiments, L² is a substituted bivalent C₄hydrocarbon chain. In some embodiments, L² is an unsubstituted bivalentC₄ hydrocarbon chain.

In some embodiments, L² is an optionally substituted bivalent C₅hydrocarbon chain wherein one or two methylene units of L² areoptionally and independently replaced with —O—, —S—, or —N(R′)—. In someembodiments, L² is a substituted bivalent C₅ hydrocarbon chain whereinone or two methylene units of L² are optionally and independentlyreplaced with —O—, —S—, or —N(R′)—. In some embodiments, L² is anunsubstituted bivalent C₅ hydrocarbon chain wherein one or two methyleneunits of L² are optionally and independently replaced with —O—, —S—, or—N(R′)—. In some embodiments, L² is a substituted bivalent C₅hydrocarbon chain. In some embodiments, L² is an unsubstituted bivalentC₅ hydrocarbon chain.

In some embodiments, L² is an optionally substituted bivalent C₆hydrocarbon chain wherein one or two methylene units of L² areoptionally and independently replaced with —O—, —S—, or —N(R′)—. In someembodiments, L² is a substituted bivalent C₆ hydrocarbon chain whereinone or two methylene units of L² are optionally and independentlyreplaced with —O—, —S—, or —N(R′)—. In some embodiments, L² is anunsubstituted bivalent C₆ hydrocarbon chain wherein one or two methyleneunits of L² are optionally and independently replaced with —O—, —S—, or—N(R′)—. In some embodiments, L² is a substituted bivalent C₆hydrocarbon chain. In some embodiments, L² is an unsubstituted bivalentC₆ hydrocarbon chain.

In some embodiments, two substituents of L² are optionally takentogether to form optionally substituted bivalent 3-8 membered saturatedor partially unsaturated carbocyclylene. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 3-8 membered saturated or partially unsaturated carbocyclylene.In some embodiments, two substituents of L² are optionally takentogether to form optionally substituted bivalent 3-8 membered saturatedcarbocyclylene. In some embodiments, two substituents of L² are takentogether to form optionally substituted bivalent 3-8 membered saturatedcarbocyclylene. In some embodiments, two substituents of L² areoptionally taken together to form optionally substituted bivalent 3-8membered partially unsaturated carbocyclylene. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 3-8 membered partially unsaturated carbocyclylene.

In some embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 3-membered saturated or partiallyunsaturated carbocyclylene. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 3-memberedsaturated carbocyclylene. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 3-memberedpartially unsaturated carbocyclylene. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 4-membered saturated or partially unsaturated carbocyclylene.In some embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 4-membered saturated carbocyclylene. Insome embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 4-membered partially unsaturatedcarbocyclylene. In some embodiments, two substituents of L² are takentogether to form optionally substituted bivalent 5-membered saturated orpartially unsaturated carbocyclylene. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 5-membered saturated carbocyclylene. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 5-membered partially unsaturated carbocyclylene. In someembodiments, two substituents of L² are taken together to formoptionally substituted bivalent 6-membered saturated or partiallyunsaturated carbocyclylene. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 6-memberedsaturated carbocyclylene. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 6-memberedpartially unsaturated carbocyclylene. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 7-membered saturated or partially unsaturated carbocyclylene.In some embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 7-membered saturated carbocyclylene. Insome embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 7-membered partially unsaturatedcarbocyclylene. In some embodiments, two substituents of L² are takentogether to form optionally substituted bivalent 8-membered saturated orpartially unsaturated carbocyclylene. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 8-membered saturated carbocyclylene. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 8-membered partially unsaturated carbocyclylene.

In some embodiments, two substituents of L² are optionally takentogether to form optionally substituted bivalent 3-8 membered saturatedor partially unsaturated heterocyclylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, two substituents of L² are taken together to formoptionally substituted bivalent 3-8 membered saturated or partiallyunsaturated heterocyclylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 3-8 membered saturated heterocyclylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, two substituents of L² are taken together to formoptionally substituted bivalent 3-8 membered partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 3-membered saturated or partiallyunsaturated heterocyclylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 3-membered saturated heterocyclylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, two substituents of L² are taken together to formoptionally substituted bivalent 3-membered partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 4-memberedsaturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 4-membered saturated heterocyclylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, two substituents of L² are taken togetherto form optionally substituted bivalent 4-membered partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 5-memberedsaturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 5-membered saturated heterocyclylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, two substituents of L² are taken togetherto form optionally substituted bivalent 5-membered partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 6-memberedsaturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 6-membered saturated heterocyclylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, two substituents of L² are taken togetherto form optionally substituted bivalent 6-membered partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 7-memberedsaturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 7-membered saturated heterocyclylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, two substituents of L² are taken togetherto form optionally substituted bivalent 7-membered partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 8-memberedsaturated or partially unsaturated heterocyclylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 8-membered saturated heterocyclylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, two substituents of L² are taken togetherto form optionally substituted bivalent 8-membered partially unsaturatedheterocyclylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 3-8 membered saturated or partiallyunsaturated heterocyclylene having one heteroatom selected fromnitrogen, oxygen, or sulfur. In some embodiments, two substituents of L²are taken together to form optionally substituted bivalent 3-8 memberedsaturated or partially unsaturated heterocyclylene having twoheteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, two substituents of L² are taken together to formoptionally substituted bivalent 3-8 membered saturated or partiallyunsaturated heterocyclylene having three heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, twosubstituents of L² are taken together to form optionally substitutedbivalent 3-8 membered saturated or partially unsaturated heterocyclylenehaving four heteroatoms independently selected from nitrogen, oxygen, orsulfur.

In some embodiments, one or two methylene units of L² are replaced with—O—. In some embodiments, one methylene unit of L² is replaced with —O—.In some embodiments, L² is an optionally substituted bivalent C₃hydrocarbon chain wherein one methylene unit of L² is replaced with —O—.In some embodiments, L² is a substituted bivalent C₃ hydrocarbon chainwherein one methylene unit of L² is replaced with —O—. In someembodiments, L² is an unsubstituted bivalent C₃ hydrocarbon chainwherein one methylene unit of L² is replaced with —O—. In someembodiments, L² is an optionally substituted bivalent C₄ hydrocarbonchain wherein one methylene unit of L² is replaced with —O—. In someembodiments, L² is a substituted bivalent C₄ hydrocarbon chain whereinone methylene unit of L² is replaced with —O—. In some embodiments, L²is an unsubstituted bivalent C₄ hydrocarbon chain wherein one methyleneunit of L² is replaced with —O—. In some embodiments, L² is anoptionally substituted bivalent C₅ hydrocarbon chain wherein onemethylene unit of L² is replaced with —O—. In some embodiments, L² is asubstituted bivalent C₅ hydrocarbon chain wherein one methylene unit ofL² is replaced with —O—. In some embodiments, L² is an unsubstitutedbivalent C₅ hydrocarbon chain wherein one methylene unit of L² isreplaced with —O—. In some embodiments, L² is an optionally substitutedbivalent C₆ hydrocarbon chain wherein one methylene unit of L² isreplaced with —O—. In some embodiments, L² is a substituted bivalent C₆hydrocarbon chain wherein one methylene unit of L² is replaced with —O—.In some embodiments, L² is an unsubstituted bivalent C₆ hydrocarbonchain wherein one methylene unit of L² is replaced with —O—.

In some embodiments, one or two methylene units of L² are replaced with—S—. In some embodiments, one methylene unit of L² is replaced with —S—.In some embodiments, L² is an optionally substituted bivalent C₃hydrocarbon chain wherein one methylene unit of L² is replaced with —S—.In some embodiments, L² is a substituted bivalent C₃ hydrocarbon chainwherein one methylene unit of L² is replaced with —S—. In someembodiments, L² is an unsubstituted bivalent C₃ hydrocarbon chainwherein one methylene unit of L² is replaced with —S—. In someembodiments, L² is an optionally substituted bivalent C₄ hydrocarbonchain wherein one methylene unit of L² is replaced with —S—. In someembodiments, L² is a substituted bivalent C₄ hydrocarbon chain whereinone methylene unit of L² is replaced with —S—. In some embodiments, L²is an unsubstituted bivalent C₄ hydrocarbon chain wherein one methyleneunit of L² is replaced with —S—. In some embodiments, L² is anoptionally substituted bivalent C₅ hydrocarbon chain wherein onemethylene unit of L² is replaced with —S—. In some embodiments, L² is asubstituted bivalent C₅ hydrocarbon chain wherein one methylene unit ofL² is replaced with —S—. In some embodiments, L² is an unsubstitutedbivalent C₅ hydrocarbon chain wherein one methylene unit of L² isreplaced with —S—. In some embodiments, L² is an optionally substitutedbivalent C₆ hydrocarbon chain wherein one methylene unit of L² isreplaced with —S—. In some embodiments, L² is a substituted bivalent C₆hydrocarbon chain wherein one methylene unit of L² is replaced with —S—.In some embodiments, L² is an unsubstituted bivalent C₆ hydrocarbonchain wherein one methylene unit of L² is replaced with —S—.

In some embodiments, one or two methylene units of L² are replaced with—N(R′)—. In some embodiments, one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is an optionally substituted bivalentC₃ hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is a substituted bivalent C₃hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is an unsubstituted bivalent C₃hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is an optionally substituted bivalentC₄ hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is a substituted bivalent C₄hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is an unsubstituted bivalent C₄hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is an optionally substituted bivalentC₅ hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is a substituted bivalent C₅hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is an unsubstituted bivalent C₅hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is an optionally substituted bivalentC₆ hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is a substituted bivalent C₆hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—. In some embodiments, L² is an unsubstituted bivalent C₆hydrocarbon chain wherein one methylene unit of L² is replaced with—N(R′)—.

In some embodiments, each substituent of L² is C₁₋₆ aliphatic. In someembodiments, each substituent of L² is C₁₋₆ alkyl. In some embodiments,each substituent of L² is methyl.

In some embodiments, L² is —CH₂CH₂O—. In some embodiments, -L²-R³ is—CH₂CH₂O—R³. In some embodiments, L² is —CH₂CH₂CH₂O—. In someembodiments, -L²-R³ is —CH₂CH₂CH₂O—R³. In some embodiments, -L²-R³ is

In some embodiments, L² is —CH₂CH(CH₃)CH₂O—. In some embodiments, -L²-R³is —CH₂CH(CH₃)CH₂O—R³.

As defined generally above, each R′ of formula I, II, III, IV, V, VI, orVII is independently hydrogen or optionally substituted C₁₋₄ alkyl. Insome embodiments, R′ is hydrogen. In some embodiments, R′ is optionallysubstituted C₁₋₄ alkyl. In some embodiments, R′ is substituted C₁₋₄alkyl. In some embodiments, R′ is unsubstituted C₁₋₄ alkyl. In someembodiments, R′ is optionally substituted methyl. In some embodiments,R′ is substituted methyl. In some embodiments, R′ is methyl. In someembodiments, R′ is optionally substituted ethyl. In some embodiments, R′is substituted ethyl. In some embodiments, R′ is ethyl. In someembodiments, R′ is optionally substituted propyl. In some embodiments,R′ is optionally substituted n-propyl. In some embodiments, R′ isoptionally substituted isopropyl. In some embodiments, R′ is substitutedpropyl. In some embodiments, R′ is substituted n-propyl. In someembodiments, R′ is substituted isopropyl. In some embodiments, R′ ispropyl. In some embodiments, R′ is n-propyl. In some embodiments, R′ isisopropyl. In some embodiments, R′ is optionally substituted butyl. Insome embodiments, R′ is substituted butyl. In some embodiments, R′ isbutyl. In some embodiments, R′ is optionally substituted n-butyl. Insome embodiments, R′ is substituted n-butyl. In some embodiments, R′ isn-butyl. In some embodiments, R′ is optionally substituted isobutyl. Insome embodiments, R′ is substituted isobutyl. In some embodiments, R′ isisobutyl. In some embodiments, R′ is optionally substituted sec-butyl.In some embodiments, R′ is substituted sec-butyl. In some embodiments,R′ is sec-butyl. In some embodiments, R′ is optionally substitutedt-butyl. In some embodiments, R′ is substituted t-butyl. In someembodiments, R′ is t-butyl.

As defined generally above, R³ of formula I or H is an optionallysubstituted ring selected from a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, phenyl, an 8-10 memberedbicyclic aromatic carbocyclic ring, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R³ is substituted. In some embodiments, R³ isunsubstituted.

In some embodiments, R³ is an optionally substituted 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ring. In someembodiments, R³ is an optionally substituted 3-membered saturated orpartially unsaturated monocyclic carbocyclic ring. In some embodiments,R³ is an optionally substituted 4-membered saturated or partiallyunsaturated monocyclic carbocyclic ring. In some embodiments, R³ is anoptionally substituted 5-membered saturated or partially unsaturatedmonocyclic carbocyclic ring. In some embodiments, R³ is an optionallysubstituted 6-membered saturated or partially unsaturated monocycliccarbocyclic ring. In some embodiments, R³ is an optionally substituted7-membered saturated or partially unsaturated monocyclic carbocyclicring. In some embodiments, R³ is an optionally substituted 8-memberedsaturated or partially unsaturated monocyclic carbocyclic ring.

In some embodiments, R³ is an optionally substituted 3-8 memberedsaturated monocyclic carbocyclic ring. In some embodiments, R³ is anoptionally substituted cycloheptyl. In some embodiments, R³ is anoptionally substituted cyclohexyl. In some embodiments, R³ is anoptionally substituted cyclopentyl. In some embodiments, R³ is anoptionally substituted cyclobutyl. In some embodiments, R³ is anoptionally substituted cyclopropyl.

In some embodiments, R³ is an optionally substituted 3-8 memberedunsaturated monocyclic carbocyclic ring. In some embodiments, R³ is anoptionally substituted cycloheptenyl. In some embodiments, R³ is anoptionally substituted cyclohexenyl. In some embodiments, R³ is anoptionally substituted cyclopentenyl. In some embodiments, R³ is anoptionally substituted cyclobutenyl.

In some embodiments, R³ is optionally substituted phenyl. In someembodiments, R³ is substituted phenyl. In some embodiments, R³ isunsubstituted phenyl. In some embodiments, R³ is3,5-dimethyl-4-chlorophenyl.

In some embodiments, R³ is an optionally substituted 8-10 memberedbicyclic aromatic carbocyclic ring. In some embodiments, R³ is asubstituted 8-10 membered bicyclic aromatic carbocyclic ring. In someembodiments, R³ is an unsubstituted 8-10 membered bicyclic aromaticcarbocyclic ring. In some embodiments, R³ is an optionally substituted10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R³is a substituted 10-membered bicyclic aromatic carbocyclic ring. In someembodiments, R³ is an unsubstituted 10-membered bicyclic aromaticcarbocyclic ring. In some embodiments, R³ is optionally substitutednaphthyl. In some embodiments, R³ is substituted naphthyl. In someembodiments, R³ is unsubstituted naphthyl. In some embodiments, R³ isoptionally substituted 1-naphthyl. In some embodiments, R³ is1-naphthyl. In some embodiments, R³ is optionally substituted2-naphthyl. In some embodiments, R³ is 2-naphthyl.

In some embodiments, R³ is an optionally substituted 3-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.In some embodiments, R³ is an optionally substituted 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.In some embodiments, R³ is a substituted 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen or sulfur. Insome embodiments, R³ is an unsubstituted 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, R³ is an optionally substituted 3-8 memberedsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen or sulfur. In some embodiments, R³ is anoptionally substituted 4-8 membered saturated heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.In some embodiments, R³ is a substituted 4-8 membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R³ is an unsubstituted4-8 membered saturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, R³ is an optionally substituted 3-memberedsaturated heterocyclic ring having one heteroatom selected fromnitrogen, oxygen or sulfur. Exemplary R³ groups include but are notlimited to optionally substituted aziridinyl, thiiranyl or oxiranyl. Insome embodiments, R³ is a substituted 3-membered saturated heterocyclicring having one heteroatom selected from nitrogen, oxygen or sulfur. Insome embodiments, R³ is an unsubstituted 3-membered saturatedheterocyclic ring having one heteroatom selected from nitrogen, oxygenor sulfur.

In some embodiments, R³ is an optionally substituted 4-memberedsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Exemplary R³ groups includebut are not limited to optionally substituted azetidinyl, oxetanyl,thietanyl, oxazetidinyl, thiazetidinyl, or diazetidinyl.

In some embodiments, R³ is an optionally substituted 5-memberedsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Exemplary R³ groups includebut are not limited to optionally substituted pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, dioxolanyl,oxathiolanyl, thiazolidinyl, dithiolanyl, imidazolidinyl,isothiazolidinyl, pyrazolidinyl, isoxazolidinyl, or thiazolidinyl.

In some embodiments, R³ is an optionally substituted 6-memberedsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Exemplary R³ groups includebut are not limited to optionally substituted piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl,thiomorpholinyl, dithianyl, dioxanyl, and oxathianyl.

In some embodiments, R³ is optionally substituted 7-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R³ groups include but are notlimited to optionally substituted azepanyl, oxepanyl, thiepanyl,diazepanyl, oxazepanyl, thiazepanyl, dioxepanyl, oxathiepanyl, ordithiepanyl.

In some embodiments, R³ is optionally substituted 8-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R³ is an optionally substituted 4-8 memberedpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In certainembodiments, R³ is an optionally substituted 5-7 membered partiallyunsaturated ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, R³ is an optionallysubstituted 5-6 membered partially unsaturated ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, R³ is an optionally substituted 5-memberedpartially unsaturated ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Exemplary R³ groups include but arenot limited to optionally substituted dihydroimidazolyl,dihydrothiazolyl, dihydrooxazolyl, or oxazolinyl. In certainembodiments, R³ is an optionally substituted 6-membered partiallyunsaturated ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R³ groups include but are notlimited to optionally substituted dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl,tetrahydropyrazinyl, dihydrodioxinyl, dihydrooxathiinyl,dihydrooxazinyl, dihydrodithiine, dihydrothiazine, dioxinyl, oxathiinyl,oxazinyl, dithiinyl, or thiazinyl. In certain embodiments, R³ is anoptionally substituted 7-membered partially unsaturated ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur.Exemplary R³ groups include but are not limited to optionallysubstituted azepinyl, oxepinyl, thiepinyl, diazepinyl, oxazepinyl,thiazepinyl, triazepinyl, oxadiazepinyl, thiadiazepinyl,dihydroazepinyl, dihydrooxepinyl, dihydrothiepinyl, dihydrodiazepinyl,dihydrooxazepinyl, dihydrothiazepinyl, tetrahydroazepinyl,tetrahydrooxepinyl, tetrahydrothiepinyl, tetrahydrodiazepinyl,tetrahydrooxazepinyl or tetrahydrothiazepinyl. In some embodiments, R³is an optionally substituted 8-membered partially unsaturated ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, R³ is an optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R³ is asubstituted 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R³ is an unsubstituted 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R³ is an optionally substituted 5-memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen or sulfur. In some embodiments, R³ is asubstituted 5-membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen or sulfur. Insome embodiments, R³ is an unsubstituted 5-membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R³ is an optionallysubstituted 6-membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R³ is a substituted 6-membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R³ is an unsubstituted6-membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, R³ is an optionally substituted 5-memberedheteroaryl ring having one heteroatom selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is selected from optionally substitutedpyrrolyl, furanyl, or thienyl.

In some embodiments, R³ is an optionally substituted 5-memberedheteroaryl ring having two heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, R³ is an optionallysubstituted 5-membered heteroaryl ring having one nitrogen atom, and anadditional heteroatom selected from sulfur or oxygen. Exemplary R³groups include but are not limited to optionally substituted pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl.

In some embodiments, R³ is an optionally substituted 5-memberedheteroaryl ring having three heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R³ groups include but are notlimited to optionally substituted triazolyl, oxadiazolyl orthiadiazolyl.

In some embodiments, R³ is an optionally substituted 5-memberedheteroaryl ring having four heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary R³ groups include but are notlimited to optionally substituted tetrazolyl, oxatriazolyl andthiatriazolyl.

In some embodiments, R³ is a 6-membered heteroaryl ring having 1-4nitrogen atoms. In some embodiments, R³ is a 6-membered heteroaryl ringhaving 1-3 nitrogen atoms. In other embodiments, R³ is an optionallysubstituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. Insome embodiments, R³ is an optionally substituted 6-membered heteroarylring having four nitrogen atoms. In some embodiments, R³ is anoptionally substituted 6-membered heteroaryl ring having three nitrogenatoms. In some embodiments, R³ is an optionally substituted 6-memberedheteroaryl ring having two nitrogen atoms. In certain embodiments, R³ isan optionally substituted 6-membered heteroaryl ring having one nitrogenatom. Exemplary R³ groups include but are not limited to optionallysubstituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,or tetrazinyl.

In some embodiments, R³ is an optionally substituted 8-10 memberedbicyclic heteroaryl ring having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, R³ is asubstituted 8-10 membered bicyclic heteroaryl ring having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R³ is an unsubstituted 8-10 membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R³ is an optionallysubstituted 8-membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R³ is a substituted 8-membered bicyclic heteroaryl ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is an unsubstituted 8-membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R³ is an optionallysubstituted 9-membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R³ is a substituted 9-membered bicyclic heteroaryl ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is an unsubstituted 9-membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R³ is an optionallysubstituted 10-membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R³ is a substituted 10-membered bicyclic heteroaryl ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is an unsubstituted 10-membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R³ is an optionally substituted 5,6-fusedheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R³ is an optionallysubstituted 5,6-fused heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R³ is an optionally substituted 5,6-fused heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is an optionally substituted 5,6-fusedheteroaryl ring having two heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R³ is optionallysubstituted 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl,4H-thieno[3,2-b]pyrrolyl, furo[3,2-b]furanyl, thieno[3,2-b]furanyl,thieno[3,2-b]thienyl, 1H-pyrrolo[1,2-a]imidazolyl,pyrrolo[2,1-b]oxazolyl or pyrrolo[2,1-b]thiazolyl. In some embodiments,R³ is an optionally substituted 5,6-fused heteroaryl ring having threeheteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R³ is optionally substituted dihydropyrroloimidazolyl,1H-furoimidazolyl, 1H-thienoimidazolyl, furooxazolyl, furoisoxazolyl,4H-pyrrolooxazolyl, 4H-pyrroloisoxazolyl, thienooxazolyl,thienoisoxazolyl, 4H-pyrrolothiazolyl, furothiazolyl, thienothiazolyl,1H-imidazoimidazolyl, imidazooxazolyl or imidazo[5,1-b]thiazolyl. Insome embodiments, R³ is an optionally substituted 5,6-fused heteroarylring having four heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R³ is an optionally substituted5,6-fused heteroaryl ring having five heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, R³ is an optionally substituted 5,6-fusedheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In other embodiments, R³ is an optionallysubstituted 5,6-fused heteroaryl ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, R³ is an optionally substituted 5,6-fused heteroaryl ringhaving one heteroatom independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is optionally substituted indolyl. Insome embodiments, R³ is optionally substituted benzofuranyl. In someembodiments, R³ is optionally substituted benzo[b]thienyl. In certainembodiments, R³ is an optionally substituted 5,6-fused heteroaryl ringhaving two heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is optionally substituted azaindolyl. Insome embodiments, R³ is optionally substituted benzimidazolyl. In someembodiments, R³ is optionally substituted benzothiazolyl. In someembodiments, R³ is optionally substituted benzoxazolyl. In someembodiments, R³ is an optionally substituted indazolyl. In certainembodiments, R³ is an optionally substituted 5,6-fused heteroaryl ringhaving three heteroatoms independently selected from nitrogen, oxygen,or sulfur. In some embodiments, R³ is optionally substitutedoxazolopyridiyl, thiazolopyridinyl or imidazopyridinyl. In certainembodiments, R³ is an optionally substituted 5,6-fused heteroaryl ringhaving four heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is optionally substituted purinyl,oxazolopyrimidinyl, thiazolopyrimidinyl, oxazolopyrazinyl,thiazolopyrazinyl, imidazopyrazinyl, oxazolopyridazinyl,thiazolopyridazinyl or imidazopyridazinyl. In certain embodiments, R³ isan optionally substituted 5,6-fused heteroaryl ring having fiveheteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R³ is an optionally substituted 6,6-fusedheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R³ is an optionallysubstituted 6,6-fused heteroaryl ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In otherembodiments, R³ is an optionally substituted 6,6-fused heteroaryl ringhaving one heteroatom selected from nitrogen, oxygen, or sulfur. In someembodiments, R³ is optionally substituted quinolinyl. In someembodiments, R³ is optionally substituted isoquinolinyl. In someembodiments, R³ is an optionally substituted 6,6-fused heteroaryl ringhaving two heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is optionally substituted quinazolinyl,phthalazinyl, quinoxalinyl or naphthyridinyl. In some embodiments, R³ isan optionally substituted 6,6-fused heteroaryl ring having threeheteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R³ is optionally substituted pyridopyrimidinyl,pyridopyridazinyl, pyridopyrazinyl, or benzotriazinyl. In someembodiments, R³ is an optionally substituted 6,6-fused heteroaryl ringhaving four heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R³ is optionally substitutedpyridotriazinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl,pyridazinopyridazinyl, pyrimidopyridazinyl or pyrimidopyrimidinyl. Insome embodiments, R³ is an optionally substituted 6,6-fused heteroarylring having five heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As defined generally above, R⁴ of formula I or II is selected from R,halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂,—S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′,—N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R⁴ is R. In some embodiments, R⁴ is hydrogen. Insome embodiments, R⁴ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R⁴ is C₁₋₆ alkyl. In some embodiments, R⁴ is methyl.

In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is —F. Insome embodiments, R⁴ is —Cl. In some embodiments, R⁴ is —Br. In someembodiments, R⁴ is —I.

In some embodiments, R⁴ is —CN. In some embodiments, R⁴ is —NO₂. In someembodiments, R⁴ is —C(O)OR′. In some embodiments, R⁴ is —OR′. In someembodiments, R⁴ is —SR′. In some embodiments, R⁴ is —C(O)N(R′)₂. In someembodiments, R⁴ is —N(R′)₂. In some embodiments, R⁴ is —S(O)₂N(R)₂. Insome embodiments, R⁴ is —N(R′)S(O)₂CF₃. In some embodiments, R⁴ is—C(O)R′. In some embodiments, R⁴ is —N(R′)C(O)R′. In some embodiments,R⁴ is —S(O)R′. In some embodiments, R⁴ is —S(O)₂R′. In some embodiments,R⁴ is —N(R′)C(O)OR. In some embodiments, R⁴ is —N(R′)S(O)₂R′.

As defined generally above, R⁵ of formula I, II, III, IV, V, VI, or VIIis selected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R⁵ is R. In some embodiments, R⁵ is hydrogen. Insome embodiments, R⁵ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R⁵ is C₁₋₆ alkyl. In some embodiments, R⁵ is methyl.

In some embodiments, R⁵ is halogen. In some embodiments, R⁵ is —F. Insome embodiments, R⁵ is —Cl. In some embodiments, R⁵ is —Br. In someembodiments, R⁵ is —I.

In some embodiments, R⁵ is —CN. In some embodiments, R⁵ is —NO₂. In someembodiments, R⁵ is —C(O)OR′. In some embodiments, R⁵ is —OR′. In someembodiments, R⁵ is —SR′. In some embodiments, R⁵ is —C(O)N(R′)₂. In someembodiments, R⁵ is —N(R′)₂. In some embodiments, R⁵ is —S(O)₂N(R)₂. Insome embodiments, R⁵ is —N(R′)S(O)₂CF₃. In some embodiments, R⁵ is—C(O)R′. In some embodiments, R⁵ is —N(R′)C(O)R′. In some embodiments,R⁵ is —S(O)R′. In some embodiments, R⁵ is —S(O)₂R′. In some embodiments,R⁵ is —N(R′)C(O)OR. In some embodiments, R⁵ is —N(R′)S(O)₂R′.

As defined generally above, R⁶ of formula I, II, III, IV, V, VI, or VIIis selected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R⁶ is R. In some embodiments, R⁶ is hydrogen. Insome embodiments, R⁶ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R⁶ is optionally substituted C₁₋₆ alkyl. In someembodiments, R⁶ is substituted C₁₋₆ alkyl. In some embodiments, R⁶ isunsubstituted C₁₋₆ alkyl. In some embodiments, R⁶ is methyl. In someembodiments, R⁶ is C₁₋₆ alkyl optionally substituted with one or morehalogen. In some embodiments, R⁶ is C₁₋₆ haloalkyl. In some embodiments,R⁶ is —CF₃. In some embodiments, R⁶ is optionally substituted C₃₋₆cycloalkyl. In some embodiments, R⁶ is substituted C₃₋₆ cycloalkyl. Insome embodiments, R⁶ is unsubstituted C₃₋₆ cycloalkyl. In someembodiments, R⁶ is optionally substituted cyclopropyl. In someembodiments, R⁶ is substituted cyclopropyl. In some embodiments, R⁶ isunsubstituted cyclopropyl. In some embodiments, R⁶ is optionallysubstituted cyclobutyl. In some embodiments, R⁶ is substitutedcyclobutyl. In some embodiments, R⁶ is unsubstituted cyclobutyl. In someembodiments, R⁶ is optionally substituted cyclopentyl. In someembodiments, R⁶ is substituted cyclopentyl. In some embodiments, R⁶ isunsubstituted cyclopentyl. In some embodiments, R⁶ is optionallysubstituted cyclohexyl. In some embodiments, R⁶ is substitutedcyclohexyl. In some embodiments, R⁶ is unsubstituted cyclohexyl.

In some embodiments, R⁶ is halogen. In some embodiments, R⁶ is —F. Insome embodiments, R⁶ is —Cl. In some embodiments, R⁶ is —Br. In someembodiments, R⁶ is —I.

In some embodiments, R⁶ is —CN. In some embodiments, R⁶ is —NO₂. In someembodiments, R⁶ is —C(O)OR′. In some embodiments, R⁶ is —OR′. In someembodiments, R⁶ is —SR′. In some embodiments, R⁶ is —C(O)N(R′)₂. In someembodiments, R⁶ is —N(R′)₂. In some embodiments, R⁶ is —S(O)₂N(R)₂. Insome embodiments, R⁶ is —N(R′)S(O)₂CF₃. In some embodiments, R⁶ is—C(O)R′. In some embodiments, R⁶ is —N(R′)C(O)R′. In some embodiments,R⁶ is —S(O)R′. In some embodiments, R⁶ is —S(O)₂R′. In some embodiments,R⁶ is —N(R′)C(O)OR. In some embodiments, R⁶ is —N(R′)S(O)₂R′.

As defined generally above, R⁷ of formula I, II, III, IV, or V ishydrogen, halogen, —CN, —NO₂, —C(O)OR, —OCF₃, —OR, —SR, —S(O)₂OR,—P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂, —N(R)S(O)₂CF₃,—C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR, —S(O)₂N(R)C(O)N(R)₂, —C(O)R,—C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R, —OC(O)N(R)₂, —C(NR)N(R)₂,—N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R, —N(R)C(O)OR, or —N(R)S(O)₂R, or anoptionally substituted group selected from C₁₋₆ aliphatic or a ringselected from a 3-8 membered saturated or partially unsaturatedcarbocyclic ring, phenyl, a 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, an 8-14 membered bicyclic or polycyclic saturated,partially unsaturated or aryl ring, a 7-14 membered bicyclic orpolycyclic saturated or partially unsaturated heterocyclic ring having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁷ is selected from R, halogen, —CN, —NO₂, —C(O)OR,—OCF₃, —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂, —N(R)₂, —S(O)₂N(R)₂,—N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR, —S(O)₂N(R)C(O)N(R)₂,—C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R, —OC(O)N(R)₂,—C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R, —N(R)C(O)OR, or—N(R)S(O)₂R.

In some embodiments, R⁷ is an optionally substituted group selected fromC₁₋₆ aliphatic or a ring selected from a 3-8 membered saturated orpartially unsaturated carbocyclic ring, phenyl, a 3-8 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, an 8-14 membered bicyclic or polycyclicsaturated, partially unsaturated or aryl ring, a 7-14 membered bicyclicor polycyclic saturated or partially unsaturated heterocyclic ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

In some embodiments, R⁷ is an optionally substituted ring selected froma 3-8 membered saturated or partially unsaturated carbocyclic ring,phenyl, a 3-8 membered saturated or partially unsaturated heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, an 8-14membered bicyclic or polycyclic saturated, partially unsaturated or arylring, a 7-14 membered bicyclic or polycyclic saturated or partiallyunsaturated heterocyclic ring having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclicor polycyclic heteroaryl ring having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁷ is an optionally substituted ring selected fromphenyl, a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, an 8-14membered bicyclic or polycyclic saturated, partially unsaturated or arylring, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁷ is R. In some embodiments, R⁷ is hydrogen.

In some embodiments, R⁷ is optionally substituted C₁₋₁₂ aliphatic. Insome embodiments, R⁷ is optionally substituted C₁₋₁₀ aliphatic. In someembodiments, R⁷ is optionally substituted C₁₋₈ aliphatic. In someembodiments, R⁷ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R⁷ is optionally substituted C₁₋₆ alkyl. In someembodiments, R⁷ is substituted C₁₋₆ alkyl. In some embodiments, R⁷ isunsubstituted C₁₋₆ alkyl. In some embodiments, R⁷ is optionallysubstituted hexyl. In some embodiments, R⁷ is substituted hexyl. In someembodiments, R⁷ is unsubstituted hexyl. In some embodiments, R⁷ isoptionally substituted pentyl. In some embodiments, R⁷ is substitutedpentyl. In some embodiments, R⁷ is unsubstituted pentyl. In someembodiments, R⁷ is optionally substituted butyl. In some embodiments, R⁷is substituted butyl. In some embodiments, R⁷ is unsubstituted butyl. Insome embodiments, R⁷ is optionally substituted propyl. In someembodiments, R⁷ is substituted propyl. In some embodiments, R⁷ isunsubstituted propyl. In some embodiments, R⁷ is optionally substitutedethyl. In some embodiments, R⁷ is substituted ethyl. In someembodiments, R⁷ is unsubstituted ethyl. In some embodiments, R⁷ isoptionally substituted methyl. In some embodiments, R⁷ is substitutedmethyl. In some embodiments, R⁷ is unsubstituted methyl.

In some embodiments, R⁷ is optionally substituted C₃₋₆ carbocyclyl. Insome embodiments, R⁷ is substituted C₃₋₆ carbocyclyl. In someembodiments, R⁷ is unsubstituted C₃₋₆ carbocyclyl. In some embodiments,R⁷ is optionally substituted cyclohexyl. In some embodiments, R⁷ issubstituted cyclohexyl. In some embodiments, R⁷ is unsubstitutedcyclohexyl. In some embodiments, R⁷ is optionally substitutedcyclopentyl. In some embodiments, R⁷ is substituted cyclopentyl. In someembodiments, R⁷ is unsubstituted cyclopentyl. In some embodiments, R⁷ isoptionally substituted cyclobutyl. In some embodiments, R⁷ issubstituted cyclobutyl. In some embodiments, R⁷ is unsubstitutedcyclobutyl. In some embodiments, R⁷ is optionally substitutedcyclopropyl. In some embodiments, R⁷ is substituted cyclopropyl. In someembodiments, R⁷ is unsubstituted cyclopropyl.

In some embodiments, R⁷ is halogen. In some embodiments, R⁷ is —F. Insome embodiments, R⁷ is —Cl. In some embodiments, R⁷ is —Br. In someembodiments, R⁷ is —I.

In some embodiments, R⁷ is —CN. In some embodiments, R⁷ is —NO₂. In someembodiments, R⁷ is —C(O)OR. In some embodiments, R⁷ is —OCF₃. In someembodiments, R⁷ is —OR. In some embodiments, R⁷ is —SR. In someembodiments, R⁷ is —S(O)₂OR. In some embodiments, R⁷ is —P(O)(OH)₂. Insome embodiments, R⁷ is —C(O)N(R). In some embodiments, R⁷ is —N(R)₂. Insome embodiments, R⁷ is —S(O)₂N(R)₂. In some embodiments, R⁷ is—N(R)S(O)₂CF₃. In some embodiments, R⁷ is —C(O)N(R)S(O)₂R. In someembodiments, R⁷ is —S(O)₂N(R)C(O)OR. In some embodiments, R⁷ is—S(O)₂N(R)C(O)N(R)₂. In some embodiments, R⁷ is —C(O)R. In someembodiments, R⁷ is —C(O)N(R)S(O)₂CF₃. In some embodiments, R⁷ is—N(R)C(O)R. In some embodiments, R⁷ is —OC(O)R. In some embodiments, R⁷is —OC(O)N(R)₂. In some embodiments, R⁷ is —C(NR)N(R)₂. In someembodiments, R⁷ is —N(R)C(NR)N(R)₂. In some embodiments, R⁷ is —S(O)R.In some embodiments, R⁷ is —S(O)₂R. In some embodiments, R⁷ is—N(R)C(O)OR. In some embodiments, R⁷ is —N(R)S(O)₂R.

In some embodiments, R⁷ is an optionally substituted 3-8 memberedsaturated or partially unsaturated carbocyclic ring. In someembodiments, R⁷ is an optionally substituted 3-membered saturated orpartially unsaturated carbocyclic ring. In some embodiments, R⁷ is anoptionally substituted 4-membered saturated or partially unsaturatedcarbocyclic ring. In some embodiments, R⁷ is an optionally substituted5-membered saturated or partially unsaturated carbocyclic ring. In someembodiments, R⁷ is an optionally substituted 6-membered saturated orpartially unsaturated carbocyclic ring. In some embodiments, R⁷ is anoptionally substituted 7-membered saturated or partially unsaturatedcarbocyclic ring. In some embodiments, R⁷ is an optionally substituted8-membered saturated or partially unsaturated carbocyclic ring.

In some embodiments, R⁷ is an optionally substituted 3-8 memberedsaturated monocyclic carbocyclic ring. In some embodiments, R⁷ is anoptionally substituted cycloheptyl. In some embodiments, R⁷ is anoptionally substituted cyclohexyl. In some embodiments, R⁷ is anoptionally substituted cyclopentyl. In some embodiments, R⁷ is anoptionally substituted cyclobutyl. In some embodiments, R⁷ is anoptionally substituted cyclopropyl.

In some embodiments, R⁷ is an optionally substituted 3-8 memberedunsaturated carbocyclic ring. In some embodiments, R⁷ is an optionallysubstituted cycloheptenyl. In some embodiments, R⁷ is an optionallysubstituted cyclohexenyl. In some embodiments, R⁷ is an optionallysubstituted cyclopentenyl. In some embodiments, R⁷ is an optionallysubstituted cyclobutenyl.

In some embodiments, R⁷ is optionally substituted phenyl. In someembodiments, R⁷ is substituted phenyl. In some embodiments, R⁷ is2-methylphenyl. In some embodiments, R⁷ is phenyl.

In some embodiments, R⁷ is an optionally substituted 3-8 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R⁷ is an optionally substituted 3-8 membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R⁷ is an optionallysubstituted 3-8 membered partially unsaturated heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Exemplary suitable embodiments for R⁷ include but are not limited tothose heterocyclic embodiments described for R.

In some embodiments, R⁷ is an optionally substituted 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R⁷ is an optionallysubstituted 5-membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R⁷ is an optionally substituted 5-membered heteroaryl ringhaving 1-4 nitrogen atoms. In some embodiments, R⁷ is optionallysubstituted pyrrolyl. In some embodiments, R⁷ is substituted pyrrolyl.In some embodiments, R⁷ is unsubstituted pyrrolyl. In some embodiments,R⁷ is optionally substituted pyrazolyl. In some embodiments, R⁷ issubstituted pyrazolyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is pyrazolyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is optionally substituted isoxazolyl. In someembodiments, R⁷ is substituted isoxazolyl. In some embodiments, R⁷ isunsubstituted isoxazolyl. In some embodiments, R⁷ is optionallysubstituted isothiazolyl. In some embodiments, R⁷ is substitutedisothiazolyl. In some embodiments, R⁷ is unsubstituted isothiazolyl. Insome embodiments, R⁷ is optionally substituted thienyl. In someembodiments, R⁷ is substituted thienyl. In some embodiments, R⁷ isunsubstituted thienyl. In some embodiments, R⁷ is optionally substitutedfuranyl. In some embodiments, R⁷ is substituted furanyl. In someembodiments, R⁷ is unsubstituted furanyl. Other exemplary suitable R⁷embodiments include but are not limited to those described for R.

In some embodiments, R⁷ is an optionally substituted 6-memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R⁷ is an optionallysubstituted 6-membered heteroaryl ring having 1-4 nitrogen atoms. Insome embodiments, R⁷ is optionally substituted pyridinyl. In someembodiments, R⁷ is substituted pyridinyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is pyridinyl. In some embodiments, R⁷ is3-pyridinyl. In some embodiments, R⁷ is 4-pyridinyl. Other exemplarysuitable R⁷ embodiments include but are not limited to those describedfor R.

In some embodiments, R⁷ is an optionally substituted 8-14 memberedbicyclic or polycyclic saturated, partially unsaturated or aryl ring. Insome embodiments, R⁷ is an optionally substituted 8-14 membered bicyclicor polycyclic saturated ring. In some embodiments, R⁷ is an optionallysubstituted 8-14 membered bicyclic or polycyclic partially saturatedring. In some embodiments, R⁷ is an optionally substituted 8-14 memberedbicyclic or polycyclic aryl ring. In some embodiments, R⁷ is anoptionally substituted 8-10 membered bicyclic saturated, partiallyunsaturated or aryl ring. In some embodiments, R⁷ is an optionallysubstituted 8-10 membered bicyclic saturated ring. In some embodiments,R⁷ is an optionally substituted 8-10 membered bicyclic partiallyunsaturated ring. In some embodiments, R⁷ is an optionally substituted8-10 membered bicyclic aryl ring. In some embodiments, R⁷ is optionallysubstituted naphthyl. In some embodiments, R⁷ is optionally substitutedanthracenyl. In some embodiments, R⁷ is optionally substituted9-anthracenyl.

In some embodiments, R⁷ is an optionally substituted 7-14 memberedbicyclic or polycyclic saturated or partially unsaturated heterocyclicring having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R⁷ is an optionally substituted7-10 membered bicyclic saturated or partially unsaturated heterocyclicring having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R⁷ is optionally substitutedindolinyl. In some embodiments, R⁷ is optionally substitutedisoindolinyl. In some embodiments, R⁷ is optionally substituted1,2,3,4-tetrahydroquinolinyl. In some embodiments, R⁷ is optionallysubstituted 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, R⁷ isan optionally substituted azabicyclo[3.2.1]octanyl.

In some embodiments, R⁷ is an optionally substituted 8-14 memberedbicyclic or polycyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R⁷ is an optionally substituted 8-14 membered bicyclic ortricyclic heteroaryl ring having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, R⁷ is anoptionally substituted 8-14 membered bicyclic heteroaryl ring having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R⁷ is an 8-10 membered bicyclic heteroaryl ring having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁷ is an optionally substituted 5,6-fusedheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R⁷ is an optionallysubstituted 5,6-fused heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R⁷ is an optionally substituted 5,6-fused heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R⁷ is an optionally substituted 5,6-fusedheteroaryl ring having two heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R⁷ is optionallysubstituted 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl,4H-thieno[3,2-b]pyrrolyl, furo[3,2-b]furanyl, thieno[3,2-b]furanyl,thieno[3,2-b]thienyl, 1H-pyrrolo[1,2-a]imidazolyl,pyrrolo[2,1-b]oxazolyl or pyrrolo[2,1-b]thiazolyl. In some embodiments,R⁷ is an optionally substituted 5,6-fused heteroaryl ring having threeheteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R⁷ is optionally substituted dihydropyrroloimidazolyl,1H-furoimidazolyl, 1H-thienoimidazolyl, furooxazolyl, furoisoxazolyl,4H-pyrrolooxazolyl, 4H-pyrroloisoxazolyl, thienooxazolyl,thienoisoxazolyl, 4H-pyrrolothiazolyl, furothiazolyl, thienothiazolyl,1H-imidazoimidazolyl, imidazooxazolyl or imidazo[5,1-b]thiazolyl. Insome embodiments, R⁷ is an optionally substituted 5,6-fused heteroarylring having four heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R⁷ is an optionally substituted5,6-fused heteroaryl ring having five heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, R⁷ is an optionally substituted 5,6-fusedheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In other embodiments, R⁷ is an optionallysubstituted 5,6-fused heteroaryl ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, R⁷ is an optionally substituted 5,6-fused heteroaryl ringhaving one heteroatom independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R⁷ is optionally substituted indolyl. Insome embodiments, R⁷ is optionally substituted benzofuranyl. In someembodiments, R⁷ is optionally substituted benzo[b]thienyl. In certainembodiments, R⁷ is an optionally substituted 5,6-fused heteroaryl ringhaving two heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R⁷ is optionally substituted azaindolyl. Insome embodiments, R⁷ is optionally substituted benzimidazolyl. In someembodiments, R⁷ is optionally substituted benzothiazolyl. In someembodiments, R⁷ is optionally substituted benzoxazolyl. In someembodiments, R⁷ is an optionally substituted indazolyl. In certainembodiments, R⁷ is an optionally substituted 5,6-fused heteroaryl ringhaving three heteroatoms independently selected from nitrogen, oxygen,or sulfur. In some embodiments, R⁷ is optionally substitutedoxazolopyridiyl, thiazolopyridinyl or imidazopyridinyl. In certainembodiments, R⁷ is an optionally substituted 5,6-fused heteroaryl ringhaving four heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R⁷ is optionally substituted purinyl,oxazolopyrimidinyl, thiazolopyrimidinyl, oxazolopyrazinyl,thiazolopyrazinyl, imidazopyrazinyl, oxazolopyridazinyl,thiazolopyridazinyl or imidazopyridazinyl. In certain embodiments, R⁷ isan optionally substituted 5,6-fused heteroaryl ring having fiveheteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R⁷ is an optionally substituted 6,6-fusedheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R⁷ is an optionallysubstituted 6,6-fused heteroaryl ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In otherembodiments, R⁷ is an optionally substituted 6,6-fused heteroaryl ringhaving one heteroatom selected from nitrogen, oxygen, or sulfur. In someembodiments, R⁷ is optionally substituted quinolinyl. In someembodiments, R⁷ is optionally substituted isoquinolinyl. In someembodiments, R⁷ is an optionally substituted 6,6-fused heteroaryl ringhaving two heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R⁷ is optionally substituted quinazolinyl,phthalazinyl, quinoxalinyl or naphthyridinyl. In some embodiments, R⁷ isan optionally substituted 6,6-fused heteroaryl ring having threeheteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R⁷ is optionally substituted pyridopyrimidinyl,pyridopyridazinyl, pyridopyrazinyl, or benzotriazinyl. In someembodiments, R⁷ is an optionally substituted 6,6-fused heteroaryl ringhaving four heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R⁷ is optionally substitutedpyridotriazinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl,pyridazinopyridazinyl, pyrimidopyridazinyl or pyrimidopyrimidinyl. Insome embodiments, R⁷ is an optionally substituted 6,6-fused heteroarylring having five heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, each of R⁴, R⁵ and R⁶ is hydrogen. In someembodiments, each of R⁴ and R⁵ is hydrogen, and R⁶ is halogen. In someembodiments, each of R⁴ and R⁵ is hydrogen, and R⁶ is —Cl. In someembodiments, each of R⁴ and R⁶ is hydrogen, and R⁵ is —Cl. In someembodiments, each of R⁴, R⁵ and R⁶ is hydrogen, and R⁷ is an optionallysubstituted ring selected from phenyl, a 5-6 membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, an 8-14 membered bicyclic or polycyclic saturated, partiallyunsaturated or aryl ring, or an 8-14 membered bicyclic or polycyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, each of R⁴ and R⁵ ishydrogen, R⁶ is halogen, and R⁷ is an optionally substituted ringselected from phenyl, a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, an8-14 membered bicyclic or polycyclic saturated, partially unsaturated oraryl ring, or an 8-14 membered bicyclic or polycyclic heteroaryl ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, each of R⁴ and R⁵ is hydrogen, R⁶ is —Cl,and R⁷ is an optionally substituted ring selected from phenyl, a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, an 8-14 membered bicyclic orpolycyclic saturated, partially unsaturated or aryl ring, or an 8-14membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each of R⁴ and R⁶ is hydrogen, R⁵ is halogen, and R⁷ is anoptionally substituted ring selected from phenyl, a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, an 8-14 membered bicyclic or polycyclicsaturated, partially unsaturated or aryl ring, or an 8-14 memberedbicyclic or polycyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each of R⁴ and R⁶ is hydrogen, R⁵ is —Cl, and R⁷ is anoptionally substituted ring selected from phenyl, a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, an 8-14 membered bicyclic or polycyclicsaturated, partially unsaturated or aryl ring, or an 8-14 memberedbicyclic or polycyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, optionally R¹ and R², R¹ and R^(2′), R¹ and R⁷, R⁴and R⁵, R⁵ and R⁶ and/or R⁶ and R⁷ of formula I, II, III, IV, V, VI, orVII are taken together with their intervening atoms to form anoptionally substituted ring selected from a 3-8 membered saturated orpartially unsaturated carbocyclic ring, phenyl, a 3-8 membered saturatedor partially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, optionally one ofR⁴ and R⁵, R⁵ and R⁶, R⁶ and R⁷, R⁷ and R¹, R¹ and R^(2′), or R² and R¹is taken together with their intervening atoms to form an optionallysubstituted ring selected from a 3-8 membered saturated or partiallyunsaturated carbocyclic ring, phenyl, a 3-8 membered saturated orpartially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, optionally one ofR⁴ and R⁵, R⁵ and R⁶, R⁶ and R⁷, R⁷ and R¹, R¹ and R^(2′), or R² and R¹is taken together with their intervening atoms to form an optionallysubstituted 3-8 membered saturated or partially unsaturated carbocyclicring. In some embodiments, optionally one of R⁴ and R⁵, R⁵ and R⁶, R⁶and R⁷, R⁷ and R¹, R¹ and R^(2′), or R² and R¹ is taken together withtheir intervening atoms to form an optionally substituted phenyl. Insome embodiments, optionally one of R⁴ and R⁵, R⁵ and R⁶, R⁶ and R⁷, R⁷and R¹, R¹ and R^(2′), or R² and R¹ is taken together with theirintervening atoms to form an optionally substituted 3-8 memberedsaturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen. In someembodiments, optionally one of R⁴ and R⁵, R⁵ and R⁶, R⁶ and R⁷, R⁷ andR¹, R¹ and R^(2′), or R² and R¹ is taken together with their interveningatoms to form an optionally substituted 5-6 membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

In some embodiments, R⁴ and R⁵ are taken together with their interveningatoms to form an optionally substituted ring selected from 3-8 memberedsaturated or partially unsaturated carbocyclic ring, phenyl, a 3-8membered saturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁵ and R⁶ are taken together with their interveningatoms to form an optionally substituted ring selected from 3-8 memberedsaturated or partially unsaturated carbocyclic ring, phenyl, a 3-8membered saturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R⁶ andR⁷ are taken together with their intervening atoms to form an optionallysubstituted ring selected from 3-8 membered saturated or partiallyunsaturated carbocyclic ring, phenyl, a 3-8 membered saturated orpartially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, R⁷ and R¹ are taken together with their interveningatoms to form an optionally substituted ring selected from a 3-8membered saturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ and R² are taken together with their interveningatoms to form an optionally substituted ring selected from a 3-8membered saturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R¹ andR² are taken together with their intervening atoms to form an optionallysubstituted ring selected from a 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 2-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroarylring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 3-8 membered saturated or partially unsaturated heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-8 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or an optionally substituted 5-6 membered heteroarylring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-8 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 5-8 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 6-8 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 6-7 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 6-membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R′ are optionallytaken together with their intervening atoms to form an optionallysubstituted 7-membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 8-membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein the R group attached to the nitrogenatom and R¹ are optionally taken together with their intervening atomsto form an optionally substituted 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an optionally substituted5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are optionally taken together withtheir intervening atoms to form an optionally substituted 4-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z),wherein the R group attached to the nitrogen atom and R¹ are takentogether with their intervening atoms to form an optionally substituted4-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z),wherein the R group attached to the nitrogen atom and R¹ are takentogether with their intervening atoms to form an optionally substituted5-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z),wherein the R group attached to the nitrogen atom and R¹ are takentogether with their intervening atoms to form an optionally substituted6-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z),wherein the R group attached to the nitrogen atom and R¹ are takentogether with their intervening atoms to form an optionally substituted6-7 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein the R group attached to the nitrogenatom and R¹ are taken together with their intervening atoms to form anoptionally substituted 4-8 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z), wherein The R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 5-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z),wherein the R group attached to the nitrogen atom and R¹ are takentogether with their intervening atoms to form an optionally substituted6-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein the R group attached to the nitrogenatom and R¹ are taken together with their intervening atoms to form anoptionally substituted 6-7 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 4-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R² is —C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z),wherein the R group attached to the nitrogen atom and R¹ are takentogether with their intervening atoms to form an optionally substituted5-membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein the R group attached to the nitrogenatom and R¹ are taken together with their intervening atoms to form anoptionally substituted 6-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 7-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R² is —C(O)N(R)-L³-R^(z) or —C(O)N(R)—C(R)₂-L³-R^(z),wherein the R group attached to the nitrogen atom and R′ are takentogether with their intervening atoms to form an optionally substituted8-membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)-L³-R^(z) or—C(O)N(R)—C(R)₂-L³-R^(z), wherein the R group attached to the nitrogenatom and R′ are taken together with their intervening atoms to form anoptionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)-L³-R^(z), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an optionally substituted5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted4-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)-L³-R^(z), wherein R¹ and the R groupare optionally taken together with their intervening atoms to form anoptionally substituted 5-8 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an optionally substituted 5-6 memberedheteroaryl ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted6-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)-L³-R^(z), wherein R¹ and the R groupare optionally taken together with their intervening atoms to form anoptionally substituted 6-7 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an optionally substituted 5-6 memberedheteroaryl ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)-L³-R^(z), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 4-8 membered saturated or partiallyunsaturated heterocyclic ring having 2-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted5-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R² is —C(O)N(R)-L³-R^(z), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 6-8 membered saturated or partiallyunsaturated heterocyclic ring having 2-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted6-7 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R² is —C(O)N(R)-L³-R^(z), wherein R′ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 4-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted5-membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R² is —C(O)N(R)-L³-R^(z), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 6-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R² is—C(O)N(R)-L³-R^(z), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted7-membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R² is —C(O)N(R)-L³-R, wherein R¹ and the R groupare optionally taken together with their intervening atoms to form anoptionally substituted 8-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)-L³-R^(z), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein R¹ and oneof the R groups are optionally taken together with their interveningatoms to form an optionally substituted 3-8 membered saturated orpartially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or anoptionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are optionally taken together withtheir intervening atoms to form an optionally substituted 3-8 memberedsaturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 3-8 memberedsaturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)—C(R)₂-L³-R, wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 4-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z),_wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 4-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 5-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 6-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 7-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 6-7 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 4-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 5-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 6-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 7-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 8-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is —C(O)N(R)—C(R)₂-L³-R^(z), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 5-6 memberedheteroaryl ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R¹ and R^(2′) are taken together with theirintervening atoms to form an optionally substituted ring selected from a3-8 membered saturated or partially unsaturated heterocyclic ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R¹ andR^(2′) are taken together with their intervening atoms to form anoptionally substituted ring selected from a 3-8 membered saturated orpartially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered heteroaryl ring having 2-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some, embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 3-8 membered saturated or partially unsaturated heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-8 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or an optionally substituted 5-6 membered heteroarylring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-8 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 5-8 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R′ are optionallytaken together with their intervening atoms to form an optionallysubstituted 6-8 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 6-7 membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 6-membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 7-membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein one R group and R¹ are optionallytaken together with their intervening atoms to form an optionallysubstituted 8-membered saturated or partially unsaturated heterocyclicring having 2-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R¹ are optionally taken together with their intervening atomsto form an optionally substituted 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an optionally substituted5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R^(2′)is —C(O)N(R)-L⁴-R^(w) or —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R¹ are optionally taken together withtheir intervening atoms to form an optionally substituted 4-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R¹ are taken together with their intervening atoms to form anoptionally substituted 4-8 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an optionally substituted 5-6 memberedheteroaryl ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w) or —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 5-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R¹ are taken together with their intervening atoms to form anoptionally substituted 6-8 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an optionally substituted 5-6 memberedheteroaryl ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w) or —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 6-7 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R¹ are taken together with their intervening atoms to form anoptionally substituted 4-8 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w) or —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein The R groupattached to the nitrogen atom and R′ are taken together with theirintervening atoms to form an optionally substituted 5-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R′ are taken together with their intervening atoms to form anoptionally substituted 6-8 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w) or —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R′ are taken together with theirintervening atoms to form an optionally substituted 6-7 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or —C(O)N(R)—C(R)₂-L⁴-R,wherein the R group attached to the nitrogen atom and R′ are takentogether with their intervening atoms to form an optionally substituted4-membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R′ are taken together with their intervening atoms to form anoptionally substituted 5-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w) or —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 6-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or —C(O)N(R)—C(R)₂-L⁴-R^(w),wherein the R group attached to the nitrogen atom and R¹ are takentogether with their intervening atoms to form an optionally substituted7-membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R¹ are taken together with their intervening atoms to form anoptionally substituted 8-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur:

In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w) or—C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R group attached to the nitrogenatom and R¹ are taken together with their intervening atoms to form anoptionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 3-8 membered saturated or partiallyunsaturated heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an optionally substituted5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R^(2′)is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted4-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)-L⁴-R, wherein R¹ and the R groupare optionally taken together with their intervening atoms to form anoptionally substituted 5-8 membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an optionally substituted 5-6 memberedheteroaryl ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w), wherein R¹ and the R group are optionally taken,together with their intervening atoms to form an optionally substituted6-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or an optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 6-7 membered saturated or partiallyunsaturated heterocyclic ring having 2-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an optionally substituted5-6 membered heteroaryl ring having 2-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 4-8 membered saturated or partiallyunsaturated heterocyclic ring having 2-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R^(2′)is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted5-8 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 6-8 membered saturated or partiallyunsaturated heterocyclic ring having 2-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, R^(2′)is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted6-7 membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 4-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted5-membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 6-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, R^(2′) is—C(O)N(R)-L⁴-R^(w), wherein R¹ and the R group are optionally takentogether with their intervening atoms to form an optionally substituted7-membered saturated or partially unsaturated heterocyclic ring having2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 8-membered saturated or partially unsaturatedheterocyclic ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)N(R)-L⁴-R^(w), wherein R¹ and the Rgroup are optionally taken together with their intervening atoms to forman optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein R¹ andone of the R groups are optionally taken together with their interveningatoms to form an optionally substituted 3-8 membered saturated orpartially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or anoptionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the Rgroup attached to the nitrogen atom and R¹ are optionally taken togetherwith their intervening atoms to form an optionally substituted 3-8membered saturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the Rgroup attached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 3-8 memberedsaturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the Rgroup attached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 4-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran optionally substituted 5-6 membered heteroaryl ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R, wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 4-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the Rgroup attached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 5-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R, wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 6-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the Rgroup attached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 7-8 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, -oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R, wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 6-7 memberedsaturated or partially unsaturated heterocyclic ring having 2-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the Rgroup attached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 4-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 5-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 6-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 7-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R^(w), wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 8-membered saturatedor partially unsaturated heterocyclic ring having 2-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is —C(O)N(R)—C(R)₂-L⁴-R, wherein the R groupattached to the nitrogen atom and R¹ are taken together with theirintervening atoms to form an optionally substituted 5-6 memberedheteroaryl ring having 2-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

As defined generally above, each R⁸ of formula III or VI isindependently selected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R⁸ is selected from R, halogen, —CN, —NO₂,—C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃,—C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and—N(R′)S(O)₂R′. In some embodiments, R⁸ is R. In some embodiments, R⁸ ishydrogen. In some embodiments, R⁸ is C₁₋₁₂ aliphatic. In someembodiments, R⁸ is C₁₋₆ aliphatic. In some embodiments, R⁸ is C₁₋₃aliphatic. In some embodiments, R⁸ is methyl.

As defined generally above, each R⁹ of formula III is independentlyselected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R⁹ is selected from R, halogen, —CN, —NO₂,—C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃,—C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and—N(R′)S(O)₂R′. In some embodiments, R⁹ is R. In some embodiments, R⁹ ishydrogen. In some embodiments, R⁹ is C₁₋₁₂ aliphatic. In someembodiments, R⁹ is C₁₋₆ aliphatic. In some embodiments, R⁹ is C₁₋₃aliphatic. In some embodiments, R⁹ is methyl.

As defined generally above, each R¹⁰ of formula IV is independentlyselected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R^(1′) is selected from R, halogen, —CN, —NO₂,—C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃,—C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and—N(R′)S(O)₂R′. In some embodiments, R¹⁰ is R. In some embodiments, R¹⁰is hydrogen. In some embodiments, R¹⁰ is C₁₋₁₂ aliphatic. In someembodiments, R¹⁰ is C₁₋₆ aliphatic. In some embodiments, R¹⁰ is C₁₋₃aliphatic. In some embodiments, R¹⁰ is methyl.

As defined generally above, each R^(w) of formula IV is independentlyselected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R^(w) is selected from R, halogen, —CN, —NO₂,—C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃,—C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and—N(R′)S(O)₂R′. In some embodiments, R^(w) is R. In some embodiments,R^(w) is hydrogen. In some embodiments, R^(w) is C₁₋₁₂ aliphatic. Insome embodiments, R^(w) is C₁₋₆ aliphatic. In some embodiments, R^(w) isC₁₋₃ aliphatic. In some embodiments, R^(w) is methyl.

As defined generally above, each R¹² of formula IV is independentlyselected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R¹² is selected from R, halogen, —CN, —NO₂,—C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃,—C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and—N(R′)S(O)₂R′. In some embodiments, R¹² is R. In some embodiments, R¹²is hydrogen. In some embodiments, R¹² is C₁₋₁₂ aliphatic. In someembodiments, R¹² is C₁₋₆ aliphatic. In some embodiments, R¹² is C₁₋₃aliphatic. In some embodiments, R¹² is methyl.

As defined generally above, each R¹³ of formula VI or VII isindependently selected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, —N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′.

In some embodiments, R¹³ is selected from R, halogen, —CN, —NO₂,—C(O)OR′, —OR′, —SR′, —C(O)N(R′)₂—N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃,—C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and—N(R′)S(O)₂R′. In some embodiments, R¹³ is R. In some embodiments, R¹³is hydrogen. In some embodiments, R¹³ is C₁₋₁₂ aliphatic. In someembodiments, R¹³ is C₁₋₆ aliphatic. In some embodiments, R¹³ is C₁₋₃aliphatic. In some embodiments, R¹³ is methyl. In some embodiments, R¹³is

In some embodiments, R¹³ is

In some embodiments, R¹³ is

Exemplary compounds are set forth in Table 1, below:

TABLE 1 Exemplary compounds.

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-25a

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

I-296

I-297

I-298

I-299

I-300

I-301

I-302

I-303

I-304

I-305

I-306

I-307

I-308

I-309

I-310

I-311

I-312

I-313

I-314

I-315

I-316

I-317

I-318

I-319

I-320

I-321

I-322

I-323

I-324

I-325

I-326

I-327

I-328

I-329

I-330

I-331

I-332

I-333

I-334

I-335

I-336

I-337

I-338

I-339

I-340

I-341

I-342

I-343

I-344

I-345

I-346

I-347

I-348

I-349

I-350

I-351

I-352

I-353

I-354

I-355

I-356

I-357

I-358

I-359

I-360

I-361

I-362

I-363

I-364

I-365

I-366

I-367

I-368

I-369

I-370

I-371

I-372

I-373

I-374

I-375

In certain embodiments, the present invention provides any compoundselected from those depicted in Table 1, above, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, a provided compound has a K_(i) value less thanabout 0.011 μM for inhibition of Mcl-1. In some embodiments, a providedcompound has a K_(i) value less than about 0.1 μM for inhibition ofMcl-1. In some embodiments, a provided compound has a K_(i) value lessthan about 0.2 μM for inhibition of Mcl-1. In some embodiments, aprovided compound has a K_(i) value less than about 0.3 μM forinhibition of Mcl-1. In some embodiments, a provided compound has aK_(i) value less than about 0.4 μM for inhibition of Mcl-1. In someembodiments, a provided compound has a K_(i) value less than about 0.5μM for inhibition of Mcl-1. In some embodiments, a provided compound hasa K_(i) value less than about 0.6 μM for inhibition of Mcl-1. In someembodiments, a provided compound has a K_(i) value less than about 0.7μM for inhibition of Mcl-1. In some embodiments, a provided compound hasa K_(i) value less than about 0.8 μM for inhibition of Mcl-1. In someembodiments, a provided compound has a K_(i) value less than about 0.9μM for inhibition of Mcl-1. In some embodiments, a provided compound hasa K_(i) value less than about 1 LM for inhibition of Mcl-1. In someembodiments, a provided compound has a K_(i) value less than about 2 μMfor inhibition of Mcl-1. In some embodiments, a provided compound has aK_(i) value less than about 3 LM for inhibition of Mcl-1. In someembodiments, a provided compound has a K_(i) value less than about 4 μMfor inhibition of Mcl-1. In some embodiments, a provided compound has aK_(i) value less than about 5 μM for inhibition of Mcl-1. Exemplaryassays for measuring K_(i) value for inhibition of Mcl-1 is widely knownin the art, including but not limited to those described in the examplesherein. In some embodiments, an assay for measuring K_(i) value forinhibition of Mcl-1 is described in Example 377.

4. Uses, Formulation and Administration and Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablesalt, ester, or salt of ester thereof and a pharmaceutically acceptablecarrier, adjuvant, or vehicle. The amount of compound in compositions ofthis invention is such that is effective to measurably inhibit Mcl-1, ina biological sample or in a patient. In certain embodiments, the amountof compound in compositions of this invention is such that is effectiveto measurably inhibit Mcl-1, in a biological sample or in a patient. Incertain embodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of Mcl-1, or a mutant thereof, activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, blood transfusion, organ transplantation, biological specimenstorage, and biological assays.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions ° may be formulated according to techniques known inthe art using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally acceptablediluent or solvent, for example as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositorie s for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract, can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor, dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In another aspect the present disclosure provides a method of treating adisease or disorder associated with the expression or over-expression ofanti-apoptotic Bcl-2 family protein members, and in certain embodimentsthose diseases characterized by the expression or the over-expression ofMcl-1 proteins, comprising administering to a mammalian patient atherapeutically effective amount of a compound of formula I, II, III,IV, V, VI, or VII, or a pharmaceutically acceptable salt or solvate or apharmaceutically acceptable carrier thereof.

Further, in accordance with the present invention, a method is providedfor preventing, modulating, or treating the progression or onset ofdiseases or disorders associated with the upregulated activity of theBcl-2 family of proteins, specifically Mcl-1 protein, such as definedabove and hereinafter, wherein a therapeutically effective amount of acompound of formula I, II, III, IV, V, VI, or VII is administered to amammalian, i.e., human, patient in need of treatment.

Another embodiment of the present invention relates to a method ofinhibiting protein kinase activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting Mcl-1, or a mutant thereof, activity in a patient comprisingthe step of administering to said patient a compound of the presentinvention, or a composition comprising said compound. In otherembodiments, the present invention provides a method for treating adisorder mediated by Mcl-1, or a mutant thereof, in a patient in needthereof, comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. Such disorders are described in detail herein.

Compounds of the present invention modulate the activity of the Bcl-2family of proteins. Preferably, compounds of the present inventioninhibit the activity of one type or a subset of anti-apoptotic Bcl-2family of proteins, for examples of Mcl-1, Bcl-2, Bcl-xL, and Bcl-wproteins. Consequently, the compounds of the present invention may beused in the treatment of multiple diseases or conditions of abnormalcell growth and/or dysregulated apoptosis; such as cancer, autoimmunedisease and pro-thrombotic conditions. Examples of diseases or disordersassociated with down-regulated apoptosis can be prevented, modulated, ortreated according to the present invention include, but are not limitedto, acoustic neuroma, acute leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma,adrenocortical cancer, angiosarcoma, astrocytoma, myelomonocytic andpromyelocytic), acute T-cell leukemia, basal cell carcinoma, bile ductcarcinoma, bladder cancer, bone cancer, brain cancer, brain stem glioma,breast cancer, bronchogenic carcinoma, cervical cancer,cholangiocarcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronicleukemia, chronic lymphocytic leukemia, chronic myelocytic(granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer,colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse largeB-cell lymphoma, duodenal cancer, dysproliferative changes (dysplasiasand metaplasias), embryonal carcinoma, endometrial cancer,endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia,esophageal cancer, estrogen-receptor positive breast cancer, essentialthrombocythemia, Ewing's tumor, fallopian tube carcinoma, fibrosarcoma,follicular lymphoma, gastric carcinoma, germ cell testicular cancer,gestational trophobalstic disease, glioblastoma, gall bladder cancer,head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma,hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, liposarcoma, lung cancer both small cell lung cancer andnon-small cell lung cancer, lymphagioendothelio-sarcoma,lymphangiosarcoma, lymphoblastic leukemia, lymphoma, including DiffuseLarge B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma, malignancies and hyperproliferative disorders ofthe bladder, breast, colon, lung, ovaries, pancreas, prostate, skin anduterus, lymphoid malignancies of T-cell or B-cell origin, leukemia,lymphoma, medullary carcinoma, medulloblastoma, melanoma (cutaneous orintraocular), meningioma, mesothelioma, multiple myeloma, myelogenousleukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, parathyroid cancer, peripheral T-cell lymphoma, pinealoma, pituitary adenoma, polycythemia vera,prostate cancer including hormone-insensitive (refractory) prostatecancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small intestine cancer, solid tumors (carcinomas and sarcomas),small cell lung cancer, spinal axis tumors, spleen cancer, stomachcancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,testicular cancer (including germ cell testicular cancer), thyroidcancer, urethra cancer, uterine cancer, Waldenstram's macroglobulinemia,testicular tumors, vaginal cancer, vulva cancer, Wilms' tumor andothers.

The compounds of the present invention possess activity as inhibitors ofthe Bcl-2 family proteins, particularly Mcl-1 protein, and, therefore,may be used in the treatment of diseases associated with anti-apoptoticBcl-2 family of proteins. Via the inhibition of the activity ofanti-apoptotic Bcl-2 family proteins, the compounds of the presentinvention may preferably be employed to release pro-apoptotic andpromote apoptosis.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of various hematologic and solidtumor types and related conditions, resistance development associatedwith chemotherapy. Consequently, it is believed that the compounds ofthe present invention may be used in preventing, inhibiting, or treatingacoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acutemyelogenous leukemia (monocytic, myeloblastic, adenocarcinoma,adrenocortical cancer, angiosarcoma, astrocytoma, myelomonocytic andpromyelocytic), acute T-cell leukemia, basal cell carcinoma, bile ductcarcinoma, bladder cancer, bone cancer, brain cancer, brain stem glioma,breast cancer, bronchogenic carcinoma, cervical cancer,cholangiocarcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronicleukemia, chronic lymphocytic leukemia, chronic myelocytic(granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer,colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse largeB-cell lymphoma, duodenal cancer, dysproliferative changes (dysplasiasand metaplasias), embryonal carcinoma, endometrial cancer,endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia,esophageal cancer, estrogen-receptor positive breast cancer, essentialthrombocythemia, Ewing's tumor, fallopian tube carcinoma, fibrosarcoma,follicular lymphoma, gastric carcinoma, germ cell testicular cancer,gestational trophobalstic disease, glioblastoma, gall bladder cancer,head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma,hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, liposarcoma, lung cancer both small cell lung cancer andnon-small cell lung cancer, lymphagioendothelio-sarcoma,lymphangiosarcoma, lymphoblastic leukemia, lymphoma, including DiffuseLarge B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma, malignancies and hyperproliferative disorders ofthe bladder, breast, colon, lung, ovaries, pancreas, prostate, skin anduterus, lymphoid malignancies of T-cell or B-cell origin, leukemia,lymphoma, medullary carcinoma, medulloblastoma, melanoma (cutaneous orintraocular), meningioma, mesothelioma, multiple myeloma, myelogenousleukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, parathyroid cancer, peripheral T-cell lymphoma, pinealoma, pituitary adenoma, polycythemia vera,prostate cancer including hormone-insensitive (refractory) prostatecancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small intestine cancer, solid tumors (carcinomas and sarcomas),small cell lung cancer, spinal axis tumors, spleen cancer, stomachcancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,testicular cancer (including germ cell testicular cancer), thyroidcancer, urethra cancer, uterine cancer, Waldenstram's macroglobulinemia,testicular tumors, vaginal cancer, vulva cancer, Wilms' tumor andothers.

It is also expected that the compounds of the present invention may beused in preventing, inhibiting, or treating pediatric cancers orneoplasms including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoidlrhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like. (commonly-owned U.S.application Ser. No. 10/988,338), Cancer Res., 2000, 60, 6101-10); andautoimmune disorders include, acquired immunodeficiency diseasesyndrome, autoimmune lymphoproliferative syndrome, hemolytic anemia,inflammatory diseases, thrombocytopenia and the like (Current Allergyand Asthma Reports 2003, 3:378-384; Bf. 1. Haematol. 2000 September;110(3): 584-90; Blood 2000 Feb. 15; 95(4):1283-92; and New EnglandJournal of Medicine 2004 September; 351(14): 1409-1418).

Involvement of Mcl-1 in acute lymphoblastic leukemia is reported inBlood (1998) 91, 991-1000.

Involvement of Mcl-1 in pancreatic carcinoma is reported in CancerChemotherapeutic Pharmacology (2008) 62, 1055-1064.

Involvement of Mcl-1 in breast cancer is reported in Anticancer Research(2004) 24, 473-482.

Involvement of Mcl-1 in breast and non small-cell lung cancer is alsoreported in Nature (2010) 463, 899-905

Involvement of Mcl-1 in non small-cell lung cancer is also reported inOncogene (2011) 30, 1963-1968

Involvement of Mcl-1 in acute myelogenous leukemia is reported in Blood(1998) 91, 991-1000.

Involvement of Mcl-1 in cervical cancer is reported in Cancer Letters(Shannon, Ireland) (2002) 180, 63-68.

Involvement of Mcl-1 in cervical cancer is also reported in MedicalOncology (2011) 3, 673-677.

Involvement of Mcl-1 in chronic lymphocytic leukemia is reported inJournal of the National Cancer Institute (2004) 96, 673-682 andImmunology (2005) 114, 441-449.

Involvement of Mcl-1 in colorectal cancer, is reported in Annals ofoncology: Official Journal of the European Society for MedicalOncology/ESMO (2001) 12, 779-785.

Involvement of Mcl-1 in gastric carcinoma, is reported in Gastric Cancer(2004) 7, 78-84.

Involvement of Mcl-1 in gestational trophobalstic disease is reported inCancer (2005) 103, 268-276.

Involvement of Mcl-1 in glioblastoma is reported in Journal ofNeurology, Neurosurgery, and Psychiatry (1999) 67, 763-768.

Involvement of Mcl-1 in head and neck cancer is reported in Archives ofOtolaryngology-Head and Neck Surgery (1999) 125, 417-422.

Involvement of Mcl-1 in lung cancer is reported in Pathology OncologyResearch: POR (1999) 5, 179-186.

Involvement of Mcl-1 in lung cancer is also reported in Cancer Biologyand Therapy (2005) 4, 267-276.

Involvement of Mcl-1 in mesothioloma, is reported in Clinical CancerResearch (1999) 5, 3508-3515.

Involvement of Mcl-1 in mesothioloma, is also reported in Carcinogenesis(2010) 6, 984-993.

Involvement of Mcl-1 in multiple myeloma is reported in European Journalof Immunology (2004) 34, 3156-3164.

Involvement of Mcl-1 in non-Hodgkin's lymphoma is reported in BritishJournal of Haematology (2002) 116, 158-161.

Involvement of Mcl-1 in oligodenroglioma is reported in Cancer (1999)86, 1832-1839.

Involvement of Mcl-1 in ovarian cancer is reported in Journal ofClinical Oncology: Official Journal of the American Society of ClinicalOncology (2000) 18, 3775-3781.

Involvement of Mcl-1 in ovarian cancer is also reported in MolecularGenetics, Gastrointestinal Carcinoma and Ovarian Carcinoma (2005) 4,479-486.

Involvement of Mcl-1 in pancreatic cancer is reported in Oncology (2002)6, 354-362.

Involvement of Mcl-1 in peripheral T-cell lymphoma is reported inJournal of Pathology (2003) 200, 240-248.

Over-expression of Bcl-2 family protein members is associated withresistance to chemotherapy and is correlated with clinical outcome,disease progression, overall prognosis or a combination thereof invarious hematologic and solid tumor types Examples of diseases ordisorders associated with the hyperactivity of the Bcl-2 family ofproteins, particularly Mcl-1, that can be prevented, modulated, ortreated according to the present invention include, but are not limitedto, acoustic neuroma, acute leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma,adrenocortical cancer, angiosarcoma, astrocytoma, myelomonocytic andpromyelocytic), acute T-cell leukemia, basal cell carcinoma, bile ductcarcinoma, bladder cancer, bone cancer, brain cancer, brain stem glioma,breast cancer, bronchogenic carcinoma, cervical cancer,cholangiocarcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronicleukemia, chronic lymphocytic leukemia, chronic myelocytic(granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer,colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse largeB-cell lymphoma, duodenal cancer, dysproliferative changes (dysplasiasand metaplasias), embryonal carcinoma, endometrial cancer,endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia,esophageal cancer, estrogen-receptor positive breast cancer, essentialthrombocythemia, Ewing's tumor, fallopian tube carcinoma, fibrosarcoma,follicular lymphoma, gastric carcinoma, germ cell testicular cancer,gestational trophobalstic disease, glioblastoma, gall bladder cancer,head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma,hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, liposarcoma, lung cancer both small cell lung cancer andnon-small cell lung cancer, lymphagioendothelio-sarcoma,lymphangiosarcoma, lymphoblastic leukemia, lymphoma, including DiffuseLarge B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma, malignancies and hyperproliferative disorders ofthe bladder, breast, colon, lung, ovaries, pancreas, prostate, skin anduterus, lymphoid malignancies of T-cell or B-cell origin, leukemia,lymphoma, medullary carcinoma, medulloblastoma, melanoma (cutaneous orintraocular), meningioma, mesothelioma, multiple myeloma, myelogenousleukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, parathyroid cancer, peripheral T-cell lymphoma, pinealoma, pituitary adenoma, polycythemia vera,prostate cancer including hormone-insensitive (refractory) prostatecancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small intestine cancer, solid tumors (carcinomas and sarcomas),small cell lung cancer, spinal axis tumors, spleen cancer, stomachcancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,testicular cancer (including germ cell testicular cancer), thyroidcancer, urethra cancer, uterine cancer, Waldenstram's macroglobulinemia,testicular tumors, vaginal cancer, vulva cancer, Wilms' tumor andothers.

It is also expected that compounds having formula I, II, III, IV, V, VI,or VII would inhibit growth of cells derived from a pediatric cancer orneoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoidlrhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

In one embodiment, a compound of the invention (e.g., a compound offormula I, II, III, IV, V, VI, or VII), or stereoisomer, geometricisomer, tautomer, solvate, metabolite, or pharmaceutically acceptablesalt, prodrug thereof, is used as an anticancer agent or as an adjunctagent for the treatment of cancer in a combination therapy. One ofordinary skill in the art is readily able to determine whether or not acandidate compound treats a cancerous condition for any particular celltype, either alone or in combination. Within certain aspects of thisembodiment, compounds of the invention are used in adjunct with othertherapies, including conventional surgery, radiotherapy andchemotherapy, for the treatment of cancer.

In another embodiment, the present invention provides for compositionsfor treating diseases in a patient during which is expressed oroverexpressed an anti-apoptotic Bcl-2 family protein, said compositionscomprising an excipient and a therapeutically effective amount of thecompound of any of formula I, II, III, IV, V, VI, or VII and atherapeutically effective amount of one additional therapeutic agent ormore than one additional therapeutic agent.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s). Further, the present invention provides a methodfor preventing, modulating, or treating the diseases as defined aboveand hereinafter, wherein a therapeutically effective amount of acombination of a compound of formula I, II, III, IV, V, VI, or VII andanother compound of formula I, II, III, IV, V, VI, or VII and/or atleast one other type of therapeutic agent, is administered to amammalian, e.g., human, patient in need of treatment.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, II, III,IV, V, VI, or VII, alone or in combination with a pharmaceutical carrieror diluent. Optionally, compounds of the present invention can be usedalone, in combination with other compounds of the invention, or incombination with one or more other therapeutic agent(s), e.g., ananticancer agent or other pharmaceutically active material.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, are optionally present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

For example, compounds of the present invention, or a pharmaceuticallyacceptable composition thereof, are administered in combination withchemotherapeutic agents to treat proliferative diseases and cancer.Examples of known chemotherapeutic agents include, but are not limitedto, Adriamycin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, taxol, interferons, platinum derivatives,taxane (e.g., paclitaxel), vinca alkaloids (e.g., vinblastine),anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g.,etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin),methotrexate, actinomycin D, dolastatin 10, colchicine, emetine,trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide,amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil,campthothecin, cisplatin, metronidazole, and Gleevec™, among others. Inother embodiments, a compound of the present invention is administeredin combination with a biologic agent, such as Avastin or VECTIBIX.

In certain embodiments, compounds of the present invention, or apharmaceutically acceptable composition thereof, are administered incombination with an antiproliferative or chemotherapeutic agent selectedfrom any one or more of abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenictrioxide, asparaginase, azacitidine, BCG Live, bevacuzimab,fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone,capecitabine, camptothecin, carboplatin, carmustine, celecoxib,cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide,cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin,dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicinhydrochloride, dromostanolone propionate, epirubicin, epoetin alfa,erlotinib, estramustine, etoposide phosphate, etoposide, exemestane,filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim,sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen,temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,zoledronate, or zoledronic acid.

Other examples of agents the inhibitors of this invention are alsocombined with include, without limitation: treatments for Alzheimer'sDisease such as donepezil hydrochloride (Aricept®) and rivastigmine(Exelon®); treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), glatirameracetate (Copaxone®), and mitoxantrone; treatments for asthma such asalbuterol and montelukast (Singulair®); agents for treatingschizophrenia such as zyprexa, risperdal, seroquel, and haloperidol;anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA,azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

In certain embodiments, compounds of the present invention, or apharmaceutically acceptable composition thereof, are administered incombination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents are optionally administered separately from aninventive compound-containing composition, as part of a multiple dosageregimen. Alternatively, those agents are optionally part of a singledosage form, mixed together with a compound of this invention in asingle composition. If administered as part of a multiple dosage regime,the two active agents are submitted simultaneously, sequentially orwithin a period of time from one another normally within five hours fromone another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention is administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a provided compound, anadditional therapeutic agent, and a pharmaceutically acceptable carrier,adjuvant, or vehicle.

The amount of both, an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above)) that is combined with the carrier materialsto produce a single dosage form will vary depending upon the hosttreated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention actsynergistically. Therefore, the amount of additional therapeutic agentin such compositions will be less than that required in a monotherapyutilizing only that therapeutic agent. In such compositions a dosage ofbetween 0.01-1,000 rig/kg body weight/day of the additional therapeuticagent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,are optionally incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects are preventedor mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

The compounds of the present invention may be employed in in adjunctwith other therapies, including conventional surgery, radiotherapy andchemotherapy, for the treatment of cancer.

Such therapies can include one or more of the following categories ofanti-cancer agents: alkylating agents, angiogenesis inhibitors,antibodies, antimetabolites, antimitotics, antiproliferatives, aurorakinase inhibitors, Bcl-2 family protein (for example, Bcl-xL, Bcl-2,Bcl-w) inhibitors, Bcr-Abl kinase inhibitors, biologic responsemodifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors,cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2)receptor inhibitors, growth factor inhibitors, heat shock protein(HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors inhibitors,hormonal therapies, inhibitors of apoptosis proteins (IAPs),immunologicals, intercalating antibiotics, kinase inhibitors, mammaliantarget of rapamycin inhibitors, mitogen-activated extracellularsignal-regulated kinase inhibitors, microRNA's, small inhibitoryribonucleic acids (siRNAs), non-steroidal anti-inflammatory drugs(NSAID's), poly ADP (adenosine diphosphate)-ribose polymerase (PARP)inhibitors, platinum chemotherapeutics, polo-like kinase inhibitors,proteasome inhibitors, purine analogs, pyrimidine analogs, receptortyrosine kinase inhibitors, retinoids/deltoids plant alkaloids,topoisomerase inhibitors and the like.

Examples of suitable alkylating agents include altretamine, AMD-473,AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone,carmustine (BCNU), chlorambucil, Cloretazine™ (VNP 40101 M),cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide,ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan,mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide,ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine),treosulfan, trofosfamide and the like.

Examples of suitable angiogenesis inhibitors includeendothelial-specific receptor tyrosine kinase (Tie-2) inhibitors,epidermal growth factor receptor (EGFR) inhibitors, insulin growthfactor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2(MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors,platelet-derived growth factor receptor (PDGFR) inhibitors,thrombospondin analogs vascular endothelial growth factor receptortyrosine kinase (VEGFR) inhibitors and the like.

Examples of suitable aurora kinase inhibitors include AZD-1152,MLN-8054, VX-680 and the like.

Examples of suitable antimetabolites include ALIMTA® (pemetrexeddisodium, L Y2315-14, MTA), 5 azacitidine, XELODA® (capecitabine),carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabineocfosfate, cytosine arabinoside, decitabine, deferoxamine,doxifluridine, eflomithine, ElCAR(5-ethynyl-1-˜-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-I, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Examples of suitable Bcl protein family member inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139 or oblimersen (Bcl-2-targetingantisense oglionucleotide)), IPI-194, IPI-565, N-(4-(4-((4′-chloro(l,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(AB T -737), N -(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-I((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl) benzenesulfonamide (ABT-263), N-(4-(4-((4′-chloro(l,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), ABT-199, GX-070 (obatoclax) and the like.

Examples of suitable Bcr-Abl kinase inhibitors include DASATINIB®(BMS-354825), GLEEVEC® (imatinib) and the like.

Examples of suitable CDK inhibitors include AZD-5438, BMI-I040, BMS-032,BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991,PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.

Examples of suitable COX-2 inhibitors include ARCOXIA® (etoricoxib),BEXTRA® (valdecoxib), BMS347070, CELEBREX™ (celecoxib), COX-189(lumiracoxib), CT-3, DERAMAXX® (deracoxib), 1TE-522,4-methyl-2-(3,4-dimethylphenyl)-I-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

Examples of suitable EGFR inhibitors include ABX-EGF, anti-EGFrimmunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, 19Aantibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OS1-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib) and the like.

Examples of suitable ErbB2 receptor inhibitors include CP-724-714,C1-I033 (canertinib), Herceptin® (trastuzumab), TYKERB® (lapatinib),OMNITARG® (2C4, petuzumab), TAK-165, GW-572016 (ionafamib), GW-282974,EKB-569, P1-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine),anti-HER12neu bispecific antibody, B7.her21gG3, AS HER2 trifunctionalbispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.

Examples of suitable histone deacetylase inhibitors includedepsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid(SAHA), TSA, valproic acid and the like.

Examples of suitable HSP-90 inhibitors include 17-AAG-nab, 17-AAG,CNF-I01, CNF-I0I0, CNF-2024, 17-DMAG, geldanamycin, 1P1-504, KOS-953,MYCOGRAB®, NCS-683664, PU24FC1, PU3, radicicol, SNX-2112, STA-9090VER49009 and the like.

Examples of suitable MEK inhibitors include ARRY-142886, ARRY-438162PD-325901, PD-98059 and the like.

Examples of suitable activators of death receptor pathway include TRAIL,antibodies or other agents that target death receptors (e.g., DR4 andDR5) such as Apomab, conatumumab, ETR2-ST01, GDC0145, lexatumumab,HGS-1029, LBY-135, PRO—1762 and trastuzumab.

Examples of suitable mTOR inhibitors include AP-23573, CC1-779,everolimus, RAD-OO1, rapamycin, temsirolimus and the like.

Examples of suitable non-steroidal anti-inflammatory drugs includeAMIGESIC® (salsalate), DOLOBID® (diflunisal), MOTRIN® (ibuprofen),ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam)ibuprofin cream, ALEVE® and NAPROSYN® (naproxen), VOLTAREN®(diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN®(tolmetm), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin)and the like.

Examples of suitable platinum chemotherapeutics include cisplatin,ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN®(carboplatin), satrap latin and the like.

Examples of suitable polo-like kinase inhibitors include B1-2536 and thelike.

Examples of suitable thrombospondin analogs include TSP-1 and the like.

Examples of suitable VEGFR inhibitors include AVASTIN® (bevacizumab),AEE-788, ANGIOZYME™, axitinib (AG-13736), AZD-2171, CP-547,632, IM-862,Macugen (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib(GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT® (sunitinib,SU-11248), VEGF trap, vatalanib, ZACTIMA (vandetanib, ZD-6474) and thelike.

Examples of suitable antibiotics include intercalating antibioticsaclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE®(bleomycin), daunorubicin, CAEL YX® or MYOCET® (doxorubicin),elsamitrucin, epirbucin, glarbuicin, ZA VEDOS® (idarubicin), mitomycinC, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin,stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and thelike.

Examples of suitable topoisomerase inhibitors include aclarubicin,9-aminocamptothecin, amonafide, BN-80915, CAMPTOSAR® (irinotecanhydrochloride) amptothecin, CARDIOXANE® (dexrazoxine), diflomotecan,edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin), etoposide,exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone,orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38,tafluposide, topotecan and the like.

Examples of suitable antibodies include AVASTIN® (bevacizumab),CD40-specific antibodies, chTNT-1/B, denosumab, ERBITUX® (cetuximab),HUMAX-CD4® (zanolimumab), IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX® (WX G250), RITUXAN® (rituximab),ticilimumab, trastuzimab and and the like.

Examples of suitable hormonal therapies include ARIMIDEX® (anastrozole),AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL®, (flutamide), EVISTA® (raloxifene), fadrozole,FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®, (letrozole),formestane, glucocorticoids, HECTOROL® or RENAGEL® (doxercalciferol),lasofoxifene, leuprolide acetate, MEGACE® (megesterol), MIFEPREX®(mifepristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen citrate),PLENAXIS™ (abarelix), predisone, PROPECIA® (finasteride), rilostane,SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone(LHRH)), vantas, VETORyL®, (trilostane or modrastane), ZOLADEX®(fosrelin, goserelin) and the like.

Examples of suitable deltoids and retinoids include seocalcitol (EB1089,CB1093), lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin),ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 andthe like.

Examples of suitable plant alkaloids include, but are not limited to,vincristine, vinblastine, vindesine, vinorelbine and the like.

Examples of suitable PARP inhibitors include olaparib, KU-59436,ABT-888, AZD-2281, AG-014699, BSI-201, BGP-15, INO-IOOI, ONO-2231 andthe like.

Examples of suitable proteasome inhibitors include VELCADE®(bortezomib), MG 132, NPI-0052, PR-171 and the like.

Examples of suitable immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-la, ACTIMMUNE® (interferon gamma-1b), or interferon gamma-nl,combinations thereof and the like. Other agents include ALFAFERONE®,BAM-002, BEROMUN® (tasonermin), BEXXAR® (tositumomab), CamPath®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine,denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocytealpha interferon, imiquimod, MDX-010, melanomavaccine, mitumomab,molgramostim, MYLOTARG™® (gemtuzumab ozogamicin). NEUPOGEN®(filgrastlm), OncoVAC-CL, OvaRex® (oregovomab), pemtumomab (Y-muHMFGl),PROVENGE®, sargaramostim, sizofilan, teceleukin, TheraCys®, ubenimex,VIRULIZIN®, Z-1OO, WF-1O, PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y -Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth,or differentiation of tissue cells to direct them to have anti-tumoractivity and include include krestin, lentinan, sizofiran, picibanilPF-3512676 (CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Examples of suitable purine analogs include LANVIS® (thioguanine) andPURI-NETHOL® (mercaptopurine).

Examples of suitable antimitotic agents include batabulin, epothilone D(KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNUI00940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO and thelike.

Compounds of the present invention can also be used as a radiosensitizerthat enhances the efficacy of radiotherapy. Examples of radiotherapyinclude, but are not limited to, external beam radiotherapy,teletherapy, brachtherapy and sealed and unsealed source radiotherapy.

Additionally, compounds having formula I or II may be combined withother chemotherapeutic agents such as ABRAXANE™ (ABI-007), ADVEXIN®,ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (polyl:poly CI2U, asynthetic RNA), APTOSYN™ (exisulind), AREDIA® (pamidronic acid),arglabin, L-asparaginase, atamestane(1-methyl-3,17-dione-androsta-1,4-diene), A V AGE® (tazarotne), AVE-8062, BEC2 (mitumomab), cachectin or cachexin (tumor necrosisfactor), canvaxin (vaccine), CeaVac™. (cancer vaccine), CELEUK®(celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX™ (humanpapillomavirus vaccine), CHOP® (C:CYTOXAN® (cyclophosphamide); H:ADRIAMYCIN® (hydroxydoxorubicin); Vincristine (ONCOVIN®); P:prednisone), CyPat™, combrestatin A4P, DAB(389)EGF or TransMID-I07R™(diphtheria toxins), dacarbazine, dactinomycin,5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON™(squalamine lactate), DIMERICINE® (T4N5 liposome lotion),discodermolide, DX-8951f(exatecan mesylate), enzastaurin, EP0906,GARDASIL® (quadrivalent human papillomavirus (Types 6, 11, 16, 18)recombinantvaccine), gastrimmune, genasense, GMK (ganglioside conjugatevaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin,hydroxycarbamide, ibandronic acid, IGN -101, IL-3-PE38, IL-13-PE38QQR(cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-a,interferon-y, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib, 5,10-25methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine),NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT®(pentostatin), ONCONASE® (aribonuclease enzyme), ONCOPHAGE® (melanomavaccine treatment), OncoVAX (IL-2Vaccine), ORATHECIN™ (rubitecan),OSIDEM® (antibody-based cell drug), OvaRex® MAb (murine monoclonalantibody), paditaxel, PANDIMEX™ (aglycone saponins from ginsengcomprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol(aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine),pegaspargase, PEGlnterferon A, phenoxodiol, procarbazine, rebimastat,REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral),SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine(Streptomyces staurospores), talabostat (PT100), TARGRETIN®(bexarotene), Taxoprexin® (DHA-paclitaxel), TELCYTA™ (TLK286),temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide,THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio) quinazolinedihydrochloride), TNFerade™ (adenovector: DNA carrier containing thegene for tumornecrosis factor-a), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alpha vbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS™ (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), zometa(zolendronic acid), zorubicin and the like.

The combination therapy can be administered as a simultaneous orsequential regimen. When administered sequentially, the combination canbe administered in two or more administrations. The combinedadministration includes co-administration, using separate formulationsor a single pharmaceutical formulation, and consecutive administrationin either order, wherein preferably there is a time period while both(or all) active agents simultaneously exert their biological activities.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or can be lowered due to the combined action(synergy) of the newly identified agent and other chemotherapeuticagents or treatments as determined by one of ordinary skill in the art.

The combination therapy can provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect can be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect can be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or in separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

The compounds of formula I, II, III, IV, V, VI, or VII can beadministered for any of the uses described herein by any suitable means,for example, orally, such as in the form of tablets, capsules, granulesor powders; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection, orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally, including administration to thenasal membranes, such as by inhalation spray; topically, such as in theform of a cream or ointment; or rectally such as in the form ofsuppositories; in dosage unit formulations containing non-toxic,pharmaceutically acceptable vehicles or diluents.

In carrying out the method of the invention for treating cancers andrelated diseases, a pharmaceutical composition will be employedcontaining the compounds of formula I, II, III, IV, V, VI, or VII, withor without other anticancer agent(s) and/or other type therapeuticagents in association with a pharmaceutical vehicle or diluent. Thepharmaceutical composition can be formulated employing conventionalsolid or liquid vehicles or diluents and pharmaceutical additives of atype appropriate to the mode of desired administration, such aspharmaceutically acceptable carriers, excipients, binders, and the like.The compounds can be administered to a mammalian patient, includinghumans, monkeys, dogs, etc. by an oral route, for example, in the formof tablets, capsules, beads, granules or powders. The dose for adults ispreferably between 1 and 2,000 mg per day, which can be administered ina single dose or in the form of individual doses from 1-4 times per day.

A typical capsule for oral administration contains compounds of formulaI, II, III, IV, V, VI, or VII (250 mg), lactose (75 mg), and magnesiumstearate (15 mg). The mixture is passed through a 60 mesh sieve andpacked into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of a compound of formula I, II, III, IV, V, VI, or VII into a vial,aseptically freeze-drying and sealing. For use, the contents of the vialare mixed with 2 mL of physiological saline, to produce an injectablepreparation.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety by reference as to the subject matterreferenced herein.

The compounds of the invention may be prepared using the exemplaryreactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effective. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including solvent,reaction atmosphere, reaction temperature, duration of the experimentand workup procedures, are chosen to be the conditions standard for thatreaction, which should be readily recognized by one skilled in the art.One having ordinary skill in the art may adjust one or more of theconditions described herein. One skilled in the art of organic synthesisunderstands that the functionality present on various portions of theedict molecule must be compatible with the reagents and reactionsproposed. Not all compounds of the invention falling into a given classmay be compatible with some of the reaction conditions required in someof the methods described. Such restrictions to the substituents, whichare compatible with the reaction conditions, will be readily apparent toone skilled in the art and alternate methods can be used.

In some embodiments, provided compounds of this invention may beprepared as shown in Scheme 1. Indole 3 can be assembled by usingJapp-Klingemann reaction described by, but not limited to, F. G.Salituro, et al. J. Med. Chem. (1990) 33, 2944-2946 as follows. Aniline1 is converted to the corresponding benzenediazonium intermediatefollowed by condensation with ethyl 2-oxocyclopentanecarboxylate to givehydrazone 2. Intramolecular Fisher indole cyclization of theintermediate 2 is followed to give indole 3. The ethyl ester functionalgroup at the flexible linker of indole 3 can be selectively reduced withexcess BH₃, and the resulting alcohol 4 can be condensed with phenols orhydroxy-heterocycles via Mitsunobu reaction to give the ether 5 using,but not limited to, DEAD or Dt-BuAD. Indole acid 6 can be generated bysaponification of compounds 5 with appropriate bases, such as Cs₂CO₃,K₂CO₃, LiOH or NaOH, at a number of conditions that are routine forthose skilled in the art of organic synthesis. Indole amides 7 can beproduced by coupling of compounds 6 with suitable amines using couplingreagents, but not limited to, PyBOP, DCC, EDC, HBTU, or TBTU at a numberof conditions that are routine for those skilled in the art of organicsynthesis.

In some embodiments, compounds of Formula 11 containing Ar or heteroarylsubstituents as R⁷ group may be synthesized by procedures illustrated inScheme 2. Compounds of Formula 8, wherein X=Cl, Br, I, triflates ordiazoderivatives, can be prepared as previously described in Scheme 1. Avariety of boronic acids 9 or borates 10, which are commerciallyavailable or can be prepared, can be coupled with intermediates 8 viae.g., Suzuki coupling protocol to afford biaryl adducts 11(Miyaura, N.,Suzuki, A., Chem. Rev. (1995), 2457). In some embodiments, one exemplarysuch procedure entails treatment of the aryl bromide or iodide 8 with anaryl boronic acid in the presence of a catalytic Pd species, such asPd(PPh₃)₄, Pd(PPh₃)₂Cl₂, Pd(OAc)₂, Pd₂(dba)₃ and a suitable ligand suchas PPh₃, AsPh₃, etc., or other such Pd catalyst, and a base such asNa₂CO₃, Cs₂CO₃, K₂CO₃, Ba(OH)₂ or Et₃N. Alternatively, biaryl adducts 11can be prepared from Pinacolborates 12 which can be prepared fromcompounds 8 via Pd, such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, Pd(OAc)₂,Pd₂(dba)₃, catalyzed coupling of bis(pinacolato)diboron. Intermediates12 can be coupled with a variety of aryl-halides or heteroaryl-halides13 using Suzuki coupling protocol described above to give compounds 11.In some embodiments, a provided approach allows for great diversity inthe subsequent coupling of indole boronic acids or borates withcommercially available haloaromatic derivatives.

In some embodiments, provided compounds of Formula 18 may be prepared byprocedures outlined in Scheme 3. Compounds of Formula 14 can be reactedwith compounds of Formula 15, wherein X is Cl, Br, I, OMs, or OTs with abase such as NaH, K₂CO₃, Cs₂CO₃, Et₃N, or DIPEA in a suitable solventsuch as DMF, THF, ether, DME, or the like, to give compounds of Formula16. Applying the same reaction sequence as described in Scheme 1,compounds of Formula 16 can undergo saponification followed by couplingreaction to give compounds of Formula 18.

In some embodiments, compounds of Formula 21 can be synthesized byprocedures depicted in Scheme 4 via selective sequential couplingreactions in one-pot. An amino group of compounds 19 can be coupled withcompounds of Formula 17 as illustrated in Scheme 1 to affordintermediates 20. In the same pot, suitable carboxylic acids can becoupled to the sulfonamide group of compounds of Formula 20 usingcoupling reagents, but not limited to, PyBOP, DCC, EDC, HBTU, or TBTU ata number of conditions that are routine for those skilled in the art oforganic synthesis, to yield acylsulfonamides of Formula 21

Alternatively, compounds of Formula 25 can be prepared by proceduresillustrated in Scheme 5 by similar sequential coupling reactions.Compounds of Formula 17 can undergo coupling reactions with an aminefunctional group of compounds 22 as shown Scheme 1 to give intermediates23. An ester group of Formula 23 can be saponificated using aqueousbased, such as Cs₂CO₃, K₂CO₃, LiOH or NaOH, at a number of conditionsthat are routine for those skilled in the art of organic synthesis togenerated compounds of Formula 24. Subsequent coupling reactions ofacids 24 with suitable sulfonamides using coupling reagents at a numberof conditions that are routine for those skilled in the art of organicsynthesis to afford reverse acylsulfonamides of Formula 25.

Exemplary method for preparing compounds of Formula 28, wherein the Niposition of indole and the amide NH is tethered to form rings, isdescribed in Scheme 6 and proceeds from compounds of Formula 26.Optionally substituted di-bromo alkanes 27 can be used to react withindole amides 26. The cyclization may be accomplished with a variety ofbases, but not limited to, DBU, Et₃N, DIPEA, Cs₂CO₃, K₂CO₃, NaH, ort-BuONa in a suitable solvent such as DMF, toluene, THF, DME, CH₃CN,1,4-dioxane or the like, to afford compounds of Formula 28 at a numberof conditions that are routine for those skilled in the art of organicsynthesis. Compounds of Formula 28 can be employed to subsequentreactions as depicted in above Schemes.

An alternate route to substituted tricyclic indole amides is shown inScheme 7 and described here. The tricyclic amide intermediates ofFormula 30 can be prepared by alkylation of the indole NH of ester 14with optionally substituted cyclic sulfamidates 29 followed bycyclization upon removal of the Boc-protecting group (see, for example,Richter H. G. F. Bioorg. Med. Chem. Lett. 2010, 5713). The size andstereochemistry of the newly formed cyclic amide can be controlled bysize and preset stereo-configuration of the reagent 29. The NH group ofFormula 30 can undergo alkylation reactions with compounds of Formula31, wherein X is Cl, Br, I, OMs, or OTs with a base such as NaH, K₂CO₃,Cs₂CO₃, Et₃N, or DIPEA in a suitable solvent such as DMF, THF, ether,DME, or the like, to give compounds of Formula 28. Correspondingcompounds of Formulae 32 and 33 can be prepared from the ester 28 bysaponification and coupling of sulfonamides to the carboxylic acidfunctional group of compounds 32 as described in Scheme 5.Alternatively, a variety of aryl or heteroaryl halides of Formula 34,wherein X is Br, I, or OTf can be coupled to the NH group of Formula 30in the presence of a catalytic Pd species, such as Pd(OAc)₂, Pd₂(dba)₃and a suitable ligand such as Xantphos and a base such as Na₂CO₃,Cs₂CO₃, or K₂CO₃ to generate compounds of Formula 35. Samesaponification and coupling of sulfonamide coupling protocols describedabove can also be applied to prepare corresponding compounds of Formulae36 and 37.

In some embodiments, compounds of Formula 39 containing tetrazole moietycan be generated by the procedure depicted in Scheme 8. A nitrile groupof compounds 38 can undergo cyclization reaction with NaN₃ in thepresence salt such as NH₃Cl, Et₃N.HCl or catalytic amount of I₂, AlCl₃or TMSCl in a suitable solvent such as DMF, PhNO₂ or NMP at a number ofconditions that are routine for those skilled in the art of organicsynthesis to give tetrazoles of Formula 39.

ABBREVIATIONS

The following abbreviations are employed in the Examples and elsewhereherein:

Dt-BuAD=di-tert-butyl azodicarboxylate

DCM=dichloromethane

EDC=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

TEA=triethylamine

DMAP=dimethylamino pyridine

HOBT=hydroxybenzotriazole

DBU=1,8-Diazabicycloundec-7-ene

DMF=dimethylformamide

DMSO=dimethylsulfoxide

THF=tetrahydrofuran

K₂CO₃=potassiumm carbonate

Cs₂CO₃=cesium carbonate

DME=1,2-dimethoxyethane

t-BuONa=sodium tert-butoxide

LDA=lithium di-isopropylamide

NaHMDS=sodium hexamethyldisilazide

LiHMDS=lithium hexamethyldisilazide

n-BuLi=n-butyl lithium

ether=diethyl ether

NaOH=sodium hydroxide

KOH=potassium hydroxide

EtOAc=ethyl acetate

Na₂CO₃=sodium carbonate

Na₂SO₄=sodium sulfate

MgSO₄=magnesium sulfate

SiO₂=silicon dioxide

CH₂C₁₂=methylene chloride

MeOH=methanol

EtOH=ethanol

Hex=hexanes

HCl=hydrochloric acid

Pd(dppf)Cl₂=[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)

Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium (O)

Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(O)

TFA=trifluoroacetic acid

Et₃N=triethylamine

DIPEA=N,N-diisopropylethylamine

SnCl₂=tin(II) chloride

DEAD=diethyl azodicarboxylate

TBAD=dit-butyl azodicarboxylate

min=minute(s)

h or hr=hour(s)

mL or ml=milliliter

g=gram(s)

mg=milligram(s)

mmol=millimole(s)

LRMS=low resolution mass spectrometry

NMR=nuclear magnetic resonance

EXAMPLES

The following Examples are offered as illustrative as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the Schemes andother methods disclosed herein or may be prepared using same.

Example 1 Preparation ofN-(tert-butyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamideI-1 Step A. Preparation of 3-(1H-indol-3-yl)propanoic acid

To a solution of indole (1.35 g, 12 mmol) and acrylic acid (1.81 mL,26.4 mmol) in acetic acid (12 mL) was added acetic anhydride (2.3 mL, 24mmol). The reaction mixture was heated at 80° C. for 7 days. Thereaction was monitored by LCMS and additional acrylic acid (0.9 mL, 12mmol) was added on day 3 and 5. The reaction mixture was concentrated invacuo, and the residue was purified by flash chromatography (Combi-flashRf Hex/EtOAc 70% gradient) to give the title compound in 1.8 g (9.5mmol). MS (ES) 190.1 (M+H).

Step B. Preparation of 3-(1H-indol-3-yl)propan-1-ol

To a solution of 3-(1H-indol-3-yl)propanoic acid (1.5 g, 7.9 mmol) inTHF (20 mL) was added 1M BH3 in THF (9 mL, 9 mmol) at 0° C. The reactionmixture was stirred for 1 h at 0° C. and quenched by addition of MeOHthen concentrated in vacuo. The residue was purified by flashchromatography (Combi-flash Rf Hexane/EtOAc gradient 0-25%) to give thetitle compound as a white solid in 1.2 g (7.1 mmol). MS (ES) 176.1(M+H).

Step C. Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole

To a solution of 3-(1H-indol-3-yl)propan-1-ol (2.54 g, 14.5 mmol), PPh₃(6.45 g, 24.6 mmol), and 3,5-diMe-4-Cl-phenol (4.0 g, 25.4 mmol) in THF(160 mL) was added Dt-BuAD (5.66 g, 24.6 mmol) at 20° C. The reactionmixture was stirred for 15 h at 20° C. then concentrated in vacuo. Theresidue was purified by flash chromatography (Combi-flash RfHexane/EtOAc gradient 0-10%) to give the desire compound as a colorlessoil in 4.5 g (14.3 mmol). MS (ES) 314.1 (M+H).

Step D. Example 1

To a solution of 3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole(115 mg, 0.37 mmol) and t-Bu-isocyanate (130 μL, 1.1 mmol) in CH₂Cl₂(0.6 mL) was added BF₃-OEt₂ (180 μL, 1.5 mmol) at 20° C. The reactionmixture was warmed to 35° C. and stirred for 15 h. The reaction wasquenched by addition of NaOAc aqueous solution. Organic layer wasseparated and concentrated. The residue was dissolved in CH₂Cl₂ (1.8 mL)and TFA (200 μL) was added at 20° C. The reaction mixture was stirredfor 15 h then concentrated. The residue was directly purified by flashchromatography (Combi-flash Rf Hexane/EtOAc gradient 0-10%) to give thetitle compound as a yellow solid in 110 mg (0.27 mmol). MS (ES) 413.2(M+H).

Example 2 Preparation of methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycinateI-2 Step A. Preparation of 6-ethoxy-6-oxo-5-(2-phenylhydrazono)hexanoicacid

To a stirring mixture of aniline (1.8 mL, 20 mmol) in 1M HCl (25 mL) andwater (5 mL) at 0° C. was added NaNO₂ (1.38 g, 20 mmol) in water (20mL), NaCH₃COOH (9.23 g, 112 mmol) in water (25 mL) and ethyl2-oxocyclopentane carboxylate (3.0 mL, 20 mmol) in sequence. Thereaction mixture was stirred for 15 min at 0° C. then warmed to 20° C.over 2 h and extracted with CH₂Cl₂, dried over MgSO₄, filtered andconcentrated in vacuo to give the title compound as a red oil in 5.2 g(90% crude).

Step B. Preparation of ethyl3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate

To a solution of 6-ethoxy-6-oxo-5-(2-phenylhydrazono)hexanoic acid (5.2g, 18 mmol) in EtOH (30 mL) was added conc. H₂SO₄ (7.5 mL), slowly. Thereaction mixture was refluxed for 1.5 h. The reaction was quenched bypouring into ice then extracted with CH₂Cl₂. The combined organic layerwas washed with sat. NaHCO₃, water, brine, dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified by flashchromatography (Combi-flash Rf Hex/EtOAc 25% gradient) to give the titlecompound as an off-white solid in 3.1 g (10.7 mmol). MS (ES) 290.1(M+H).

Step C. Preparation of ethyl 3-(3-hydroxypropyl)-1H-indole-2-carboxylate

To a solution of ethyl 3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate(1.4 g, 4.8 mmol) in THF (20 mmol) was added BH₃ in THF (20 mL, 20 mmol)at 20° C. The reaction mixture was stirred for 15 h at 20° C. andquenched by addition of MeOH then concentrated in vacuo. The residue waspurified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient0-50%) to give the title compound as a white solid in 940 mg (3.8 mmol).MS (ES) 248.1 (M+H).

Step D. Preparation of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate

To a solution of ethyl 3-(3-hydroxypropyl)-1H-indole-2-carboxylate (70mg, 0.28 mmol), PPh₃ (110 mg, 0.51 mmol) and 3,5-diMe-4-Cl-phenol (81mg, 0.52 mmol) in THF (3.5 mL) was added Dt-BuAD (99 mg, 0.51 mmol) at20° C. The reaction mixture was stirred for 15 h at 20° C. thenconcentrated in vacuo. The residue was purified by flash chromatography(Combi-flash Rf Hexane/EtOAc gradient 0-10%) to give the title compound(81 mg, 0.21 mmol) as a colorless oil. MS (ES) 385.2 (M+H).

Step E. Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid

To a solution of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (70mg, 0.18 mmol) in EtOH (2.0 mL) was added 50% NaOH H₂O solution (100 μL)at 20° C. The reaction mixture was stirred for 3 h at 20° C. thenacidified with 1N HCl solution. The mixture was extracted with EtOAc,dried over MgSO₄, filtered and concentrated in vacuo. The crude productwas purified by reverse phase prep. HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient to 95% CH₃CN 0.5% TFA) to yield the title compound(60 mg, 0.17 mmol) as a white solid. MS (ES) 358.1 (M+H).

Step F. Example 2

To a solution of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid(100 mg, 0.28 mmol) and H-Gly-OMe HCl (53 mg, 0.42 mmol) in CH₂Cl₂ (3.0mL) was added EDC.HCl (87 mg, 0.56 mmol) followed by DMAP (120 mg, 0.98mmol) at 20° C. The reaction mixture was stirred for 15 h at 20° C. thenquenched by addition of 0.5 N HCl. The quenched reaction mixture wasextracted with CH₂Cl₂, washed with brine, dried by MgSO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(Combi-flash Rf Hexane/EtOAc gradient 0-20%) to give the title compound(95 mg, 0.22 mmol) as a white solid. MS (ES) 429.2 (M+H).

Example 3 Preparation of(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycineI-3

To a solution of methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycinate(90 mg, 0.21 mmol) in EtOH (1.5 mL) was added 10% LiOH aqueous solution(150 μL, 0.63 mmol). The reaction mixture was stirred for 15 h at 20° C.then quenched by addition of 1M HCl. The reaction mixture was extractedwith CH₂Cl₂ and concentrated in vacuo. The crude product was purified byreserve phase prep. HPLC (Phenomenex Gemini C18, H₂O/CH₃CN 40-95% 0.01%TFA) to give the title product as a white solid in 75 mg (0.18 mmol). MS(ES) 415.1 (M+H).

Example 4 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(2-(methylsulfonamido)-2-oxoethyl)-1H-indole-2-carboxamideI-4

To a solution of(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycine(15 mg, 0.035 mmol) and methanesulfonamide (6.6 mmol, 0.070 mmol) inCH₂Cl₂ (1.0 mL) was added EDC HCl (11 mg, 0.070 mmol) followed by DMAP(13 mg, 0.11 mmol) at 20° C. The reaction mixture was stirred for 15 hat 20° C. then concentrated in vacuo. The residue was purified byreserve phase prep. HPLC (Phenomenex Gemini C18, H₂O/CH₃CN 30-95% 0.01%TFA) to give the title product as a white solid in 15 mg (0.030 mmol).MS (ES) 492.1 (M+H).

Example 5 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(2-oxo-2-(phenylsulfonamido)ethyl)-1H-indole-2-carboxamideI-5

Title compound was prepared (16 mg, 0.029 mmol) as a white solidaccording to procedures described in Example 4 using(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycine(15 mg, 0.035 mmol) and substituting methanesulfonamide withbenzenesulfonamide (9.0 mg, 0.70 mmol). MS (ES) 554.2 (M+H).

Example 6 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(2-oxo-2-(pyridine-3-sulfonamido)ethyl)-1H-indole-2-carboxamideI-6

Title compound was prepared (18 mg, 0.028 mmol) as an off-white solidTFA salt according to procedures described in Example 4 using(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycine(15 mg, 0.035 mmol) and substituting methanesulfonamide withpyridine-3-sulfonamide (9.0 mg, 0.70 mmol). MS (ES) 555.1 (M+H).

Example 7 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(2-(naphthalene-2-sulfonamido)-2-oxoethyl)-1H-indole-2-carboxamideI-7

Title compound was prepared (16 mg, 0.026 mmol) as a white solidaccording to procedures described in Example 4 using(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycine(15 mg, 0.035 mmol) and substituting methanesulfonamide withnaphthalene-2-sulfonamide (15.0 mg, 0.70 mmol). MS (ES) 604.2 (M+H).

Example 8 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(2-oxo-2-((4-phenoxyphenyl)sulfonamido)ethyl)-1H-indole-2-carboxamideI-8

Title compound was prepared (20 mg, 0.031 mmol) as a white solidaccording to procedures described in Example 4 using(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycine(15 mg, 0.035 mmol) and substituting methanesulfonamide with4-phenoxybenzenesulfonamide (18.0 mg, 0.70 mmol). MS (ES) 646.2 (M+H).

Example 9 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(2-(cyclopropanesulfonamido)-2-oxoethyl)-1H-indole-2-carboxamideI-9

Title compound was prepared (16 mg, 0.031 mmol) as a white solidaccording to procedures described in Example 4 using(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)glycine(15 mg, 0.035 mmol) and substituting methanesulfonamide withcyclopropanesulfonamide (9.0 mg, 0.70 mmol). MS (ES) 518.1 (M+H).

Example 10 Preparation of ethyl3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoateI-10

Title compound was prepared (112 mg, 0.24 mmol) as a white solidaccording to procedures described in Example 2 Step F using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid(100 mg, 0.28 mmol) and substituting H-Gly-OMe HCl with ethyl3-aminopropanoate hydrochloride (65 mg, 0.42 mmol). MS (ES) 457.2 (M+H).

Example 11 Preparation of3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid I-11

Title compound was prepared (90 mg, 0.21 mmol) as a white solidaccording to procedures described in Example 3 using ethyl3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoate(100 mg, 0.22 mmol). MS (ES) 429.2 (M+H).

Example 12 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(methylsulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-12

Title compound was prepared (12 mg, 0.024 mmol) as a white solidaccording to procedures described in Example 4 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol). MS (ES) 505.1 (M+H).

Example 13 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(cyclopropanesulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-13

Title compound was prepared (17 mg, 0.031 mmol) as a white solidaccording to procedures described in Example 9 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol). MS (ES) 532.2 (M+H).

Example 14 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-oxo-3-(phenylsulfonamido)propyl)-1H-indole-2-carboxamideI-14

Title compound was prepared (19 mg, 0.033 mmol) as a white solidaccording to procedures described in Example 5 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol). MS (ES) 568.2 (M+H).

Example 15 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-oxo-3-(pyridine-3-sulfonamido)propyl)-1H-indole-2-carboxamideI-15

Title compound was prepared (20 mg, 0.030 mmol) as an off-white solidTFA salt according to procedures described in Example 6 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol). MS (ES) 569.2 (M+H).

Example 16 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(naphthalene-2-sulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-16

Title compound was prepared (21 mg, 0.034 mmol) as a white solidaccording to procedures described in Example 7 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol). MS (ES) 618.2 (M+H).

Example 17 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-oxo-3-((4-phenoxyphenyl)sulfonamido)propyl)-1H-indole-2-carboxamideI-17

Title compound was prepared (19 mg, 0.029 mmol) as a white solidaccording to procedures described in Example 8 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol). MS (ES) 660.2 (M+H).

Example 18 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-((2-cyanophenyl)sulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-18

Title compound was prepared (17 mg, 0.029 mmol) as a white solidaccording to procedures described in Example 4 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol) and substituting methanesulfonamide with2-cyanobenzenesulfonamide (13 mg, 0.035 mmol). MS (ES) 593.2 (M+H).

Example 19 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-((3-cyanophenyl)sulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-19

Title compound was prepared (19 mg, 0.032 mmol) as a white solidaccording to procedures described in Example 4 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol) and substituting methanesulfonamide with3-cyanobenzenesulfonamide (13 mg, 0.035 mmol). MS (ES) 593.2 (M+H).

Example 20 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-((2-nitrophenyl)sulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-20

Title compound was prepared (18 mg, 0.029 mmol) as a white solidaccording to procedures described in Example 4 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol) and substituting methanesulfonamide with2-nitrobenzenesulfonamide (14 mg, 0.035 mmol). MS (ES) 613.2 (M+H).

Example 21 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-((3-nitrophenyl)sulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-21

Title compound was prepared (19 mg, 0.030 mmol) as a white solidaccording to procedures described in Example 4 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol) and substituting methanesulfonamide with3-nitrobenzenesulfonamide (14 mg, 0.035 mmol). MS (ES) 613.2 (M+H).

Example 22 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-((4-nitrophenyl)sulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-22

Title compound was prepared (17 mg, 0.028 mmol) as a white solidaccording to procedures described in Example 4 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)propanoicacid (15 mg, 0.035 mmol) and substituting methanesulfonamide with4-nitrobenzenesulfonamide (14 mg, 0.035 mmol). MS (ES) 613.2 (M+H).

Example 23 Preparation of3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)propanoicacid I-23 Step A. Preparation of5-(2-(2-bromophenyl)hydrazono)-6-ethoxy-6-oxohexanoic acid

Title compound was prepared as a red oil according to proceduresdescribed in Example 2 Step A using 2-bromoaniline and ethyl2-oxocyclopentane carboxylate. MS (ES) 368.0 (M+H).

Step B. Preparation of ethyl7-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate

Title compound was prepared according to procedures described in Example2 Step B using 5-(2-(2-bromophenyl)hydrazono)-6-ethoxy-6-oxohexanoicacid. MS (ES) 324.1 (M+H).

Step C. Preparation of ethyl7-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylate

Title compound was prepared according to procedures described in Example2 Step C using ethyl7-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate. MS (ES) 326.0(M+H).

Step D. Preparation of ethyl7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate

Title compound was prepared according to procedures described in Example2 Step D using ethyl 7-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylateand 4-chloro-3,5-dimethylphenol. MS (ES) 464.1 (M+H).

Step E. Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

To a solution of ethyl7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate(50 mg) in DME (837 μl), water (359 μl) and ethanol (239 μl) at 20 wasadded3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(28.7 mg), bis(triphenylphosphine)palladium(II) chloride (7.55 mg) andNa₂CO₃ (114 mg, 1.076 mmol). The mixture was then heated to 150° C. inBiotage Initiator for 30 min. After heating, LiOH (269 μl) was added tothe mixture and the mixture heated at 100° C. in Biotage Initiator for10 min. The mixture was cooled, acidified (6M HCl), extracted withEtOAc, dried (MgSO₄) and concentrated. The residue was purified byreverse phase preparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 95% CH₃CN 0.1% TFA) to yield the title compound as a whitesolid. MS (ES) 452.2 (M+H).

Step F. Preparation of ethyl3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)propanoate

Title compound was prepared (51 mg, 0.091 mmol) as a white solidaccording to procedures described in Example 10 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (64 mg, 0.14 mmol) and ethyl 3-aminopropanoate hydrochloride (26mg, 0.17 mmol). MS (ES) 551.2 (M+H).

Step G. Example 23

Title compound was prepared (40 mg, 0.076 mmol) as a white solidaccording to procedures described in Example 11 using ethyl3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)propanoate(48 mg, 0.087 mmol). MS (ES) 523.2 (M+H).

Example 24 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(3-((4-nitrophenyl)sulfonamido)-3-oxopropyl)-1H-indole-2-carboxamideI-24

Title compound was prepared (7 mg, 0.010 mmol) as a white solidaccording to procedures described in Example 4 using3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)propanoicacid (10 mg, 0.019 mmol) and 4-nitrobenzenesulfonamide (4.7 mg, 0.038mmol). MS (ES) 707.2 (M+H).

Example 25 Preparation of methyl3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoateI-25

To a stirred solution of EDC (0.243 mmol), HOBT (0.022 mmol),3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (0.221 mmol), and TEA (0.664 mmol) in DCM (0.1M) was added methyl3-(aminomethyl)benzoate hydrochloride (0.221 mmol). The reaction mixturewas stirred for 15 h then concentrated in vacuo. The residue was slurredin 1 mL of 1:1 mix of acetonitrile and methanol and filtered. Thefiltrate was purified by reverse phase preparatory HPLC (PhenomenexGemini C18, H₂O/CH₃CN gradient to 5-95% CH₃CN 0.1% TFA) to yield thetitle compound as a white solid. MS (ES) 599.2 (M+H).

Example 25a Preparation of3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-25a

To a stirred solution of methyl3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(0.2 mmol) in THF (2 mL) was added a drop of MeOH followed by an aqueoussolution of 2M LiOH (0.7 mL). The reaction was then heated at 50° C. for5 hours then cooled to room temperature. The traction mixture wasacidified to pH 2 with 3M HCl and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The resultant solid was dissolved in 1 mL of 1:1mix of acetonitrile and methanol. The slurry was filtered and thefiltrate was purified by reverse phase preparatory HPLC (PhenomenexGemini C18, H₂O/CH₃CN gradient to 5-95% CH₃CN 0.1% TFA) to yield thetitle compound (0.18 mmol) as a white solid. MS (ES) 585.2 (M+H).

Example 26 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(((2-cyanophenyl)sulfonyl)carbamoyl)benzyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-26

Title compound was prepared (11 mg, 0.014 mmol) as a white solidaccording to procedures described in Example 4 using3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid (10 mg, 0.017 mmol) and substituting methanesulfonamide with2-cyanobenzenesulfonamide (3.8 mg, 0.021 mmol). MS (ES) 748.9 (M+H).

Example 27 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(3-(((4-nitrophenyl)sulfonyl)carbamoyl)benzyl)-1H-indole-2-carboxamideI-27

Title compound was prepared (11 mg, 0.014 mmol) as a white solidaccording to procedures described in Example 4 using3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid (10 mg, 0.017 mmol) and substituting methanesulfonamide with4-nitrobenzenesulfonamide (4.2 mg, 0.021 mmol). MS (ES) 769.0 (M+H).

Example 28 Preparation of methyl3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoateI-28 Step A. Preparation of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

To a solution of ethyl7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate(300 mg, 0.64 mmol) in dioxane (3.0 ml) and water (2.0 ml) at 20 wasadded1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(168 mg, 0.71 mmol), Pd(PPh₃)₄ (37 mg, 0.032 mmol) and K₂CO₃ (267 mg,1.94 mmol). The mixture was degased then heated to 125° C. in BiotageInitiator for 40 min. The reaction was quenched by addition of water,extracted with EtOAc, dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography (Combi-flash RfHexane/EtOAc gradient 0-15%) to give the title compound (175 mg, 0.35mmol) as a white solid. MS (ES) 494.2 (M+H)

Step B. Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

To a solution of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(175 mg, 0.35 mmol) in EtOH (1.6 mL) and THF (0.4 mL) was added 2Naqueous solution of LiOH (1.0 mL) then the mixture was stirred for 24 hat 40° C. The reaction mixture was concentrated in vacuo, and residuewas re-dissolved in water (1.0 mL). The solution was acidified (6M HCl),and white solid was filtered to give the title compound (160 mg, 0.34mmol). MS (ES) 466.2 (M+H).

Step C. Example 28

A mixture of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (0.055 g, 0.118 mmol), methyl 3-(aminomethyl)benzoate hydrochloride(0.024 g, 0.118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.024 g, 0.124 mmol) and DMAP (0.016 g, 0.130 mmol) inTHF (1.18 ml) was stirred at rt. After 90 min, the mixture wasconcentrated in vacuo. The residue was purified via reverse-phasepreparative HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 40-95%MeCN 0.1% TFA) to give the title compound. MS (ES) 613.0 (M+H).

Example 29 Preparation of3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-29

A mixture of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (0.055 g, 0.118 mmol), methyl 3-(aminomethyl)benzoate hydrochloride(0.024 g, 0.118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.024 g, 0.124 mmol) and DMAP (0.016 g, 0.130 mmol) inTHF (1.18 ml) was stirred at rt. After 15 h, LiOH (2M, 1.0 ml) and EtOH(0.5 ml) were added and the mixture was warmed to 60° C. After 3 h, themixture was acidified (1M HCl), extracted with EtOAc, dried, filteredand concentrated in vacuo. The residue was purified via reverse-phasepreparative HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 40-95%MeCN 0.1% TFA) to give the title compound. MS (ES) 599.1 (M+H).

Example 30 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(((3-cyanophenyl)sulfonyl)carbamoyl)benzyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-30

A mixture of3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid (0.025 g, 0.042 mmol), 3-cyanobenzenesulfonamide (0.011 g, 0.063mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.012 g, 0.063 mmol) and DMAP (7.65 mg, 0.063 mmol) in dichloromethane(0.835 ml) was stirred at rt. After 90 min, the mixture was concentratedin vacuo. The residue was purified via reverse-phase preparative HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient to 50-95% MeCN 0.1% TFA) togive the title compound. MS (ES) 763.0. (M+H).

Example 31 Preparation of3-((10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-31

A mixture of methyl3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(0.035 g, 0.057 mmol), 1,2-dibromoethane (0.017 ml, 0.200 mmol) andcesium carbonate (0.074 g, 0.228 mmol) in DMF (0.571 ml) was stirred at100° C. After 48 h, the mixture was concentrated in vacuo. A mixture ofthe intermediate ester and LiOH (2M, 0.285 ml) in THF (0.3 ml) and EtOH(0.15 ml) was stirred at 50° C. After 15 h, the mixture was acidified(1M HCl), extracted with EtOAc, dried, filtered and concentrated invacuo. The residue was purified via reverse-phase preparative HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient to 50-80% MeCN 0.1% TFA) togive the title compound. MS (ES) 625.0 (M+H).

Example 32 Preparation of3-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-32

Title compound was prepared (18 mg, 0.013 mmol) as a white solidaccording to procedures described in Example 31 using3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(0.01 g, 0.016 mmol), and substituting 1,2-dibromoethane1,3-dibromopropane (8.28 μl, 0.082 mmol). MS (ES) 639.1 (M+H). ¹H NMR(400 MHz, CDCl₃): 8.04 (m, 2H), 7.73 (d, J=7.2 Hz, 1H), 7.63 (d, J=7.7Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 6.94 (d, J=6.3Hz, 1H), 6.65 (s, 2H), 4.77 (s, 2H), 4.02 (t, J=6.3 Hz, 2H), 3.89 (m,5H), 3.25 (m, 4), 2.35 (s, 6H), 2.26 (t, J=6.6 Hz, 2H), 2.11 (s, 6H),1.53 (m, 2).

Example 33 Preparation of3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-33 Step A. Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

To a solution of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(0.081 g, 0.164 mmol) in DMF (1.09 ml) at rt was added sodium hydride(0.016 g, 0.394 mmol). After 15 min, dimethyl sulfate (0.047 ml, 0.492mmol) was added to the mixture. After 5 h, the mixture was concentratedin vacuo. A mixture of the crude ester and LiOH (2M, 0.820 ml) in EtOH(0.547 ml) and THF (1.09 ml) was stirred at 60° C. After 6 h, themixture was acidified (1M HCl), extracted with EtOAc, dried, filteredand concentrated in vacuo. The residue was purified via reverse-phasepreparative HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 40-95%MeCN 0.1% TFA) to give the title compound. MS (ES) 480.1 (M+H).

Step B. Example 33

A mixture of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (0.010 g, 0.021 mmol), methyl 3-(aminomethyl)benzoate hydrochloride(4.62 mg, 0.023 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (4.39 mg, 0.023 mmol) and DMAP (2.80 mg, 0.023 mmol) inTHF (0.208 ml) was stirred at rt. After 5 h, the mixture wasconcentrated in vacuo. A mixture of the intermediate ester and LiOH (2M,0.177 ml) in THF (0.208 ml) and EtOH (0.100 ml) was stirred at 60° C.After 3 h, the mixture was acidified (1M HCl), extracted with EtOAc,dried, filtered and concentrated in vacuo. The residue was purified viareverse-phase preparative HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 40-80% MeCN 0.1% TFA) to give the title compound. MS (ES)613.0 (M+H). ¹H NMR (400 MHz, CDCl₃): 7.99 (m, 2H), 7.68 (d, J=7.6 Hz,1H), 7.52 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.25 (t, J=6.0 Hz,1H), 7.18 (t, J=7.4 Hz, 1H), 6.98 (d, J=6.5 Hz, 1H), 6.50 (s, 2H), 4.68(m, 2H), 4.00 (s, 3H), 3.91 (t, J=5.4 Hz, 2H), 3.47 (s, 3H), 3.21 (t,J=6.1 Hz, 2H), 2.27 (m, 8H), 2.22 (s, 3H), 2.17 (s, 3H).

Example 34 Preparation of3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,5-dimethyl-3-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-34 Step A. Preparation of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate

To a solution of ethyl7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate(0.84 g) in DMF (9.0 ml) was added bis(pinacolato)diboron (0.551 g),potassium acetate (0.82 g) and Pd(dppf)Cl₂ (66 mg). The mixture waswarmed to 60° C. After 15 h, the mixture was concentrated in vacuo. Theresidue was taken up in CH₂Cl₂, washed with H₂O, filtered andconcentrated in vacuo. The crude residue was purified by flash columnchromatography (Combi-Flash Rf, Hex/EtOAc 0-10% gradient) to give thetitle compounds. MS (ES) 512.2 (M+H).

Step B. Preparation of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

To a solution of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate(0.79 g) in DME (5.8 ml) and ethanol (2.9 ml) was added(4-bromo-1,5-dimethyl-1H-pyrazol-3-yl)methanol (0.348 g), Pd(PPh₃)₄ (89mg) and cesium fluoride (0.703 g). The mixture was heated to 120° C. inBiotage Initiator for 45 min. The crude residue was purified by flashcolumn chromatography (Combi-Flash Rf, CH₂Cl₂/MeOH 0-10% gradient) togive the title compounds. MS (ES) 510.3 (M+H).

Step C. Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,5-dimethyl-3-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

To a solution of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(0.23 g, 0.451 mmol) and N,N-diisopropylethylamine (0.236 ml, 1.353mmol) in dichloromethane (3.39 ml) at 0° C. was added methanesulfonylchloride (0.070 ml, 0.902 mmol). After 30 min, pyrrolidine (0.186 ml,2.255 mmol) was added to the mixture. The mixture was then warmed to rt.After 15 h at rt, the reaction mixture was diluted with dichloromethane.The combined organics were washed with H₂O, filtered and concentrated invacuo. A mixture of the crude ester intermediate and LiOH (2N, 2.2 ml,4.51 mmol) in THF (2.0 ml) and EtOH (1.0 ml) was stirred at 60° C. After3 h, the mixture was acidified (1M HCl), extracted with EtOAc, dried,filtered and concentrated in vacuo. The residue was purified viareverse-phase preparative HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 40-80% MeCN 0.1% NH₄OH) to give the title compound. MS (ES)535.2 (M+H).

Step C. Example 34

A mixture of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,5-dimethyl-3-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (0.028 g, 0.052 mmol), methyl 3-(aminomethyl)benzoate (0.011 g,0.068 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(10.53 mg, 0.055 mmol) and DMAP (7.03 mg, 0.058 mmol) in THF (0.52 ml)was stirred at rt. After 15 h, LiOH (0.445 ml, 0.890 mmol) was added tothe mixture. The mixture was then warmed to 60° C. After 3 h, themixture was acidified (1M HCl), extracted with EtOAc, dried, filteredand concentrated in vacuo. The residue was purified via reverse-phasepreparative HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 30-70%MeCN 0.1% NH₄₀OH) to give the title compound. MS (ES) 668.1 (M+H).

Example 35 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(((2-cyanophenyl)sulfonyl)carbamoyl)benzyl)-7-(1,5-dimethyl-3-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-35

A mixture of3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,5-dimethyl-3-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid (0.013 g, 0.019 mmol), 2-cyanobenzenesulfonamide (5.32 mg, 0.029mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.59mg, 0.029 mmol) and DMAP (3.57 mg, 0.029 mmol) in dichloromethane (0.389ml) was stirred at rt. After 15 h, the mixture was concentrated invacuo. The residue was purified via reverse-phase preparative HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient to 20-80% MeCN 0.1% NH₄OH) togive the title compound. MS (ES) 832.0 (M+H).

Example 36 Preparation of3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxamido)benzoicacid I-36 Step A: Preparation of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxylate

A solution of ethyl7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate(60 mg, 0.129 mmol), (2-methylpyridin-3-yl)boronic acid (20 mg, 0.15mmol), Pd(PPh₃)₄ (7.46 mg, 6.45 μmol) and CsF (58.8 mg, 0.387 mmol) inethanol (0.22 ml) and DME (0.44 ml) was degassed under Argon for 10 min.The mixture was then heated to 120° C. in Biotage Initiator for 25 min.The reaction mixture was concentrated under vacuum, and the residue waspurified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient0-15%) to yield the title compound (59 mg). MS(ES) 477.3 (M+H).

Step B: Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxylicacid

A solution of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxylate(38 mg, 0.080 mmol) and LiOH (2N, 200 μl, 0.4 mmol) in EtOH (400 μl) andTHF (100 μl) was heated to 40° C. for 16 h. The reaction mixture wasconcentrated in vacuo, and the residue was purified by reverse phaseprep. HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 95% CH₃CN 0.1%TFA) to yield the title compound (32 mg 0.071 mmol). MS (ES) 449.2(M+H).

Step C: Example 36

A solution of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxylicacid (20 mg, 0.045 mmol), methyl 3-aminobenzoate (7.4 mg, 0.049 mmol),EDC (9.4 mg, 0.049 mmol) and DMAP (1.1 mg, 8.91 μmol) in CH₂Cl₂ (890 μl)was stirred 15 h at rt. The solvent was removed and the residue wasdissolved in a mixture of LiOH (2N, 0.1 ml, 0.2 mmol), EtOH (0.4 ml) andTHF (0.1 ml). The reaction mixture was stirred at 40° C. for 16 h. Thereaction mixture was cooled to rt and concentrated in vacuo. The residuewas purified by reverse phase prep. HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient to 30-80% CH₃CN 0.1% TFA) to give the title compound(12.6 mg) as a white solid. MS (ES) 568.0 (M+H).

Example 37 Preparation of4-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxamido)benzoicacid I-37

The title compound was prepared (22 mg, 0.039 mmol) according toprocedures described in Example 36 Step A and B using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxylicacid (30 mg, 0.067 mmol) and substituting methyl 3-aminobenzoate withmethyl 4-aminobenzoate (11 mg, 0.074 mmol). MS (ES) 568.0 (M+H).

Example 38 Preparation of4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-38 Step A. Preparation of ethyl7-bromo-6-chloro-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate

Title compounds were prepared according to procedures described inExample 2 Step A and B using 2-bromo-3-chloroaniline. MS (ES) 402.0(M+H).

Step B. Preparation of ethyl7-bromo-6-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate

Title compound was prepared according to the procedure in Example 2 StepC using ethyl7-bromo-6-chloro-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate. MS(ES) 360.1 (M+H).

Step C. Preparation ethyl7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate

Title compound was prepared as a colorless oil according to proceduresdescribed in Example 2 Step D using7-bromo-6-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate. MS (ES)498.0 (M+H).

Step D. Preparation of ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

Title compound was prepared as a colorless oil according to proceduresdescribed in Example 28 Step A using7-bromo-6-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate. MS (ES)528.2 (M+H).

Step E. Preparation of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

Title compound was prepared as a colorless oil according to proceduresdescribed in Example 28 Step B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate.MS (ES) 500.2 (M+H).

Step F. Example 38

The title compound was prepared (15 mg, 0.024 mmol) according toprocedures described in Example 36 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.080 mmol) and methyl 4-aminobenzoate (13.29 mg, 0.088mmol). MS (ES) 619.0 (M+H).

Example 39 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-39

The title compound was prepared (16 mg, 0.026 mmol) according toprocedures described in Example 36 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.040 mmol) and methyl 3-aminobenzoate (6.65 mg, 0.044mmol). MS (ES) 619.2 (M+H).

Example 40 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-phenyl-1H-indole-2-carboxamideI-40

To a stirred solution of EDC (0.088 mmol), HOBT (0.014 mmol),3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid(0.07 mmol) in DCM (0.1M) and TEA (0.28 mmol) was added aniline (0.077mmol). The reaction mixture was allowed to stir for 15 hours. Uponcompletion the volatiles were removed via rotary evaporation and theremaining material slurried in 1 mL of 1:1 mix of acetonitrile andmethanol. The slurry was filtered and the filtrate was purified byreverse phase preparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 5-95% CH₃CN 0.1% TFA) to yield the title compound as a whitesolid. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 9.10 (br s, 1H), 8.35 (br s,1H), 7.68 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz,1H), 7.36-7.31 (m, 3H), 7.17 (2, J=6.0 Hz, 2H), 6.56 (s, 2H), 4.01 (t,J=6.0 Hz, 2H), 2.34-2.25 (m, 2H), 2.25 (s, 6H); MS (ES) 433.2 (M+H).

Example 41 Preparation ofN-benzyl-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamideI-41

Title compound was prepared according to the procedure used in Example40 using the requisite amine. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 9.06 (brs, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.32-7.24 (m,5H), 7.19-7.12 (m, 2H), 6.44 (s, 2H), 4.57 (d, J=4.0 Hz, 2H), 3.88 (t,J=6.0 Hz, 2H), 3.25 (t, J=6 Hz, 2H), 2.26 (s, 6H), 2.24-2.18 (m, 2H); MS(ES) 447.3 (M+H). MS (ES) 447.2 (M+H).

Example 42 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-phenethyl-1H-indole-2-carboxamideI-42

Title compound was prepared according to the procedure used in Example40 using the requisite amine. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 9.02 (brs, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.32-7.27 (m,3H), 7.24-7.10 (m, 4H), 6.71 (br t, J=4.0 Hz, 1H), 6.57 (s, 2H), 3.81(t, J=6.0 Hz, 2H), 3.60 (q, J=6.0 Hz, 2H), 3.09 (t, J=8.0 Hz, 2H), 2.83(t, J=8.0 Hz, 2H), 2.33 (s, 6H), 2.12-2.05 (m, 2H); MS (ES) 461.2 (M+H).

Example 43 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N,N-dimethyl-1H-indole-2-carboxamideI-43

Title compound was prepared according to the procedure used in Example40 using the requisite amine. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 8.41 (brs, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.27-7.24 (m,1H), 7.13 (t, J=8.0 Hz, 1H), 6.61 (s, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.08(s, 6H), 3.00 (t, J=8.0 Hz, 2H), 2.33 (s, 6H), 2.18-2.11 (m, 2H); MS(ES) 385.2 (M+H).

Example 44 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(2-(1,2-dimethyl-1H-indol-3-yl)ethyl)-1H-indole-2-carboxamideI-44

Title compound was prepared according to the procedure used in Example40 using the requisite amine. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 9.11 (brs, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0Hz, 1H), 7.30-7.22 (m, 2H), 7.17-7.09 (m, 2H), 7.04 (t, J=6.0 Hz, 1H),6.72 (br t, J=6.0 Hz, 1H), 6.53 (s, 2H), 3.68-3.60 (m, 4H), 3.60 (s,3H), 3.02 (t, J=6.0 Hz, 2H), 2.96 (t, J=8.0 Hz, 2H), 2.32 (s, 6H), 2.30(s, 3H), 1.95-1.90 (m, 2H); MS (ES) 528.3 (M+H).

Example 45 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(4-phenoxybenzyl)-1H-indole-2-carboxamideI-45

Title compound was prepared according to the procedure used in Example40 using the requisite amine. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 9.13 (brs, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.34-7.29 (m,3H), 7.22-7.08 (m, 5H), 6.99 (d, J=4.0 Hz 2H), 6.93 (d, J=12.0 Hz 2H),6.48 (s, 2H), 4.53 (d, J=6.0 Hz, 2H), 3.90 (t, J=6.0 Hz, 2H), 3.24 (t,J=8.0 Hz, 2H), 2.28 (s, 6H), 2.25-2.18 (m, 2H); MS (ES) 539.2 (M+H).

Example 46 Preparation of(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indol-2-yl)(4-phenylpiperazin-1-yl)methanoneI-46

Title compound was prepared according to the procedure used in Example40 using the requisite amine. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 8.42 (brs, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.31-7.27 (m,3H), 7.15 (t, J=8.0 Hz, 1H), 6.96-6.93 (m, 3H), 6.59 (s, 2H), 3.90 (t,J=6.0 Hz, 2H), 3.84 (br t, J=4.0 Hz, 4H), 3.21 (br t, J=4.0 Hz, 4H),3.04 (t, J=6.0 Hz, 2H), 2.29 (s, 6H), 2.19-2.12 (m, 2H); MS (ES) 502.2(M+H).

Example 47 Preparation of(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indol-2-yl)(4-morpholinopiperidin-1-yl)methanoneI-47

Title compound was prepared according to the procedure used in Example40 using the requisite amine. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 9.12 (brs, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.28 (t, J=6.0Hz 1H), 7.14 (t, J=6.0 Hz, 1H), 6.59 (s, 2H), 4.42 (br t, J=12.0 Hz,2H), 3.97-3.84 (m, 6H), 3.44-3.31 (m, 3H), 2.97 (t, J=8.0 Hz, 2H),2.97-2.79 (m, 4H), 2.32 (s, 6H), 2.14-2.01 (m, 4H), 1.84-1.75 (m, 2H);MS (ES) 510.3 (M+H).

Example 48 Preparation of tert-butyl(1-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)piperidin-4-yl)carbamateI-48

To a stirred solution of EDC (0.175 mmol), HOBT (0.028 mmol),3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid(0.07 mmol) in DCM (0.1M) and TEA (0.559 mmol) was added tert-butylpiperidin-4-ylcarbamate (0.153 mmol). The reaction mixture was allowedto stir for 15 hours. Upon completion the volatiles were removed viarotary evaporation and the remaining material adsorbed onto silica gel.The material was isolated via silica gel chromatography using a gradientup to 10% methanol in DCM to yield the Title compound as a yellow foam.MS (ES) 540.3 (M+H).

Example 49 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(5-sulfamoylpyridin-2-yl)-N-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamideI-49 Step A. Preparation of 6-chloropyridine-3-sulfonamide

To a 20 mL scintillation vial with an inlaid septum cap was added a stirbar, 6-chloropyridine-3-sulfonyl chloride (2 mmol) and 8 mL ofacetonitrile (0.25 M). The solution was cooled to −78° C. and ammoniagas was bubbled through the solution for 10 seconds. The reaction wasthen allowed to warm to room temperature, at which time the reaction wasvented with a syringe needle and allowed to stir for two hours. Theresultant white slurry was then filtered and the filtrate concentratedin vacuo to yield title compound as a white solid.

Step B. Preparation of6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide

To a suspension of 6-chloropyridine-3-sulfonamide in ethanol (0.3 M) ina microwave compatible vessel was added(4-(trifluoromethyl)phenyl)methylamine. The reaction mixture was heatedat 150° C. in Biotage Initiator for 1 hour. The reaction mixture wasquenched by addition of H₂O, extracted with EtOAc, dried over MgSO₄,filtered and concentrated in vacuo to give the title compound as anoff-white solid.

Step C. Example 49

Title compound was prepared according to the procedure used in Example40 using 6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide. MS(ES) 671.2 (M+H).

Example 50 Preparation of ethyl4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoateI-50

To a stirred solution of EDC (0.153 mmol), DMAP (0.153 mmol),3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid(0.076 mmol) in DCM (0.1M) and TEA (0.28 mmol) was added ethyl4-(piperazin-1-yl)benzoate (0.077 mmol). The reaction mixture wasallowed to stir for 15 hours. Upon completion the volatiles were removedvia rotary evaporation and the remaining material slurried in 1 mL of1:1 mix of acetonitrile and methanol. The slurry was filtered and thefiltrate was purified by reverse phase preparatory HPLC (H₂O/CH₃CNgradient to 95% CH₃CN 0.1% TFA) to yield the title compound as a whitesolid. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 8.92 (br s, 1H), 7.95 (d, J=8.0Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.37 (br s, 1H), 7.11 (d, J=8.0 Hz,1H), 6.86 (d, J=12.0 Hz, 2H), 6.55 (s, 2H), 4.35 (q, J=8.0 Hz, 2H), 3.87(t, J=6.0 Hz, 2H), 3.81 (br t, J=4.0 Hz, 4H), 3.00 (t, J=8.0 Hz, 2H),2.28 (s, 6H), 2.13-2.09 (m, 2H); MS (ES) 608.2 (M+H).

Example 51 Preparation of4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoicacid I-51

To a stirred solution of ethyl4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoate(0.123 mmol) in THF (0.075M) was added a drop of MeOH, and an aqueoussolution of 2M LiOH (1 mL). The reaction was then heated at 50° C. for15 hours, after which it was cooled to room temperature, acidified to pH2 with 3M HCl and extracted with EtOAc. The organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo. Theresultant solid was dissolved in 1 mL of 1:1 mix of acetonitrile andmethanol. The slurry was filtered and the filtrate was purified byreverse phase preparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 5-95% CH₃CN 0.1% TFA) to yield the title compound as a whitesolid. ¹H NMR (d6-DMSO 400 MHz, 25° C.): 11.48 (s, 1H), 7.79 (d, J=8.0Hz, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.05 (br d,J=12.0 Hz, 1H), 6.96 (br d, J=8.0 Hz, 2H), 6.69 (s, 2H), 3.91 (t, J=4.0Hz, 2H), 3.62 (br s, 4H), 2.90 (t, J=8.0 Hz, 2H), 2.21 (s, 6H),2.04-1.88 (m, 2H); MS (ES) 580.0 (M+H). MS (ES).

Example 52 Preparation of methyl3-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoateI-52

Title compound was prepared according to the procedure used in Example50 using the requisite amine and6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylicacid. ¹H NMR (d6-DMSO, 400 MHz, 25° C.): 7.64 (d, J=8.0 Hz, 2H), 7.46(m, 1H), 7.43-7.36 (m, 3H), 7.25-7.21 (m, 1H), 7.08-7.03 (m, 1H), 6.69(s, 2H), 3.92 (t, J=8.0 Hz, 2H), 3.83 (s, 3H), 3.64 (br s, 4H), 3.21 (brs, 4H), 2.90 (t, J=8.0 Hz, 2H), 2.20 (s, 6H), 2.04-1.96 (m, 2H); MS (ES)594.1 (M+H).

Example 53 Preparation ofN-(2-(N-(2-(4-bromophenyl)acetyl)sulfamoyl)ethyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamideI-53

To a stirred solution of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid(0.062 mmol), EDC (0.068 mmol), HOBT (0.006 mmol), and TEA (0.187 mmol)in DCM (0.1M) at 0° C. was added 2-aminoethanesulfonamide hydrochloride.The reaction mixture was then slowly warmed to room temperature andstirred for 15 hours. After the allotted time, EDC (0.125 mmol), DMAP(0.187 mmol) and 2-(4-bromophenyl)acetic acid (0.062 mmol) were added tothe reaction, and it was allowed to stir for another 15 hours. Thereaction mixture was then concentrated in vacuo, and the remainingmaterial slurried in 1 mL of 1:1 mix of acetonitrile and methanol. Theslurry was filtered and the filtrate was purified by reverse phasepreparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 5-95%CH₃CN 0.1% TFA) to yield the title compound as a white solid. MS (ES)660.1 (M+H).

Example 54 Preparation ofN-(2-(N-(2-((3r,5r,7r)-adamantan-1-yl)acetyl)sulfamoyl)ethyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamideI-54

Title compound was prepared according to the procedure used in Example53 by substituting 2-((3r,5r,7r)-adamantan-1-yl)acetic acid for2-(4-bromophenyl)acetic acid. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 9.18 (brs, 1H), 8.50 (br s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H),7.30-7.23 (m, 2H), 7.11 (t, J=6.0 Hz, 1H), 6.69 (s, 2H), 3.93 (t, J=6.0Hz, 2H), 3.88 (q, J=6.0 Hz, 2H), 3.57 (br t, J=6.0 Hz, 2H), 3.19 (t,J=8.0 Hz, 2H), 2.35 (s, 6H), 2.23-2.16 (m, 2H), 1.96-1.83 (br m, 7H),1.70-1.55 (br m, 6H); MS (ES) 640.2 (M+H).

Example 55 Preparation ofN-(2-(N-((3r,5r,7r)-adamantane-1-carbonyl)sulfamoyl)ethyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamideI-55

Title compound was prepared according to the procedure used in Example53 by substituting (3r,5r,7r)-adamantane-1-carboxylic acid for2-(4-bromophenyl)acetic acid. ¹H NMR (CDCl₃, 400 MHz, 25° C.): 9.13 (brs, 1H), 8.13 (br s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H),7.30 (t, J=6.0 Hz 1H), 7.27 (t, J=8.0 Hz 1H), 7.13 (t, J=6.0 Hz, 1H),6.68 (s, 2H), 3.93 (t, J=6.0 Hz, 2H), 3.84 (q, J=6.0 Hz, 2H), 3.55 (brt, J=6.0 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 2.34 (s, 6H), 2.24-2.19 (m,2H), 2.02 (br m, 4H), 1.83 (br m, 6H), 1.73-1.60 (br m, 6H); MS (ES)626.2 (M+H).

Example 56 Preparation of ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylateI-56

To a stirred solution of EDC (0.553 mmol), HOBT (0.05 mmol),3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid(0.503 mmol), and TEA (1.51 mmol) in DCM (0.1M) was added ethyl5-(aminomethyl)furan-2-carboxylate (0.503 mmol). The reaction mixturewas allowed to stir for 15 hours. The reaction mixture was concentratedin vacuo, and the residue was slurried in 1 mL of 1:1 mix ofacetonitrile and methanol. The slurry was filtered and the filtrate waspurified by reverse phase preparatory HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient to 5-95% CH₃CN 0.1% TFA) to yield the title compoundas a white solid. MS (ES) 509.2 (M+H).

Example 57 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylicacid I-57

To a stirred solution of ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate(0.295 mmol) in THF (0.1M) was added a drop of MeOH, and an aqueoussolution of 2M LiOH (1 mL). The reaction was then heated at 50° C. for15 hours, after which it was cooled to room temperature, acidified to pH2 with 3M HCl and extracted with ethyl acetate. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated in vacuo.The resultant solid was dissolved in 1 mL of 1:1 mix of acetonitrile andmethanol. The slurry was filtered and the filtrate was purified byreverse phase preparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 5-95% CH₃CN 0.1% TFA) to yield the title compound as a whitesolid. ¹H NMR (d6-DMSO, 400 MHz, 25° C.): 8.51 (t, J=8.0 Hz, 1H), 7.62(d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.21 (t, J=6.0 Hz, 1H), 7.15(d, J=8.0 Hz, 1H), 7.02 (t, J=6.0 Hz, 1H), 6.73 (s, 2H), 6.51 (d, J=4.0Hz, 1H), 3.92 (t, J=8.0 Hz, 2H), 3.18 (t, J=8.0 Hz, 2H), 2.26 (s, 6H),2.04-1.96 (m, 2H), MS (ES) 481.2 (M+H).

Example 58 Preparation3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((5-((2-(trifluoromethyl)benzyl)carbamoyl)furan-2-yl)methyl)-1H-indole-2-carboxamideI-58

To a stirred solution of EDC (0.125 mmol), HOBT (0.01 mmol),5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylicacid (0.062 mmol), and TEA (0.187 mmol) in DCM (0.1M) was added(2-(trifluoromethyl)phenyl)methylamine (0.075 mmol). The reactionmixture was stirred for 15 h then concentrated in vacuo. The residue wasslurred in 1 mL of 1:1 mix of acetonitrile and methanol and filtered.The filtrate was purified by reverse phase preparatory HPLC (PhenomenexGemini C18, H₂O/CH₃CN gradient to 5-95% CH₃CN 0.1% TFA) to yield thetitle compound as a white solid. ¹H NMR (d6-DMSO, 400 MHz, 25° C.):11.25 (s, 1H), 8.91 (m, 1H), 8.48 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.63(m, 2H), 7.50-7.39 (m, 3H), 7.21 (t, J=6.0 Hz, 1H), 7.17 (m, 1H), 7.02(t, J=6.0 Hz, 1H), 6.73 (s, 2H), 6.52 (m, 1H), 4.59 (m, 3H), 3.92 (t,J=8.0 Hz, 2H), 3.18 (t, J=8.0 Hz, 2H), 2.26 (s, 6H), 2.04-1.96 (m, 2H),MS (ES) 638.2 (M+H).

Example 59 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((5-((methylsulfonyl)carbamoyl)furan-2-yl)methyl)-1H-indole-2-carboxamideI-59

To a stirred solution of EDC (0.125 mmol), DMAP (0.187 mmol),5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylicacid (0.062 mmol), and TEA (0.187 mmol) in DCM (0.1M) was addedmethanesulfonamide (0.187 mmol). The reaction mixture was allowed tostir for 15 hours. The reaction mixture was stirred for 15 h thenconcentrated in vacuo. The residue was slurred in 1 mL of 1:1 mix ofacetonitrile and methanol and filtered. The filtrate was purified byreverse phase preparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 5-95% CH₃CN 0.1% TFA) to yield the title compound as a whitesolid. MS (ES) 558.1 (M+H).

Example 60 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((5-((phenylsulfonyl)carbamoyl)furan-2-yl)methyl)-1H-indole-2-carboxamideI-60

Title compound was prepared according to the procedure used in Example59 using the requisite sulfonamide. MS (ES) 620.2 (M+H).

Example 61 Preparation of ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylateI-61

Title compound was prepared according to the procedure used in Example56 by substituting3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid for3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid.¹H NMR (d6-DMSO, 400 MHz, 25° C.): 10.55 (s, 1H), 8.93 (m, 1H), 7.60 (d,J=8.0 Hz, 1H), 7.23 (d, J=4.0 Hz, 1H), 7.11-7.04 (m, 2H), 6.75 (s, 2H),6.51 (m, 1H), 4.56 (d, J=8.0 Hz, 2H), 4.26 (q, J=8.0 Hz, 2H), 3.97 (t,J=6.0 Hz, 2H), 3.24 (t, J=8.0 Hz, 2H), 2.27 (s, 6H), 2.09 (s, 6H),2.06-2.02 (m, 2H), 1.27 (t, J=8.0 Hz, 3H), MS (ES) 603.2 (M+H).

Example 62 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylicacid I-62

Title compound was prepared according to the procedure used in Example57 by substituting ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 575.2 (M+H).

Example 63 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-N-((5-(hydroxymethyl)furan-2-yl)methyl)-1H-indole-2-carboxamideI-63

To a stirred solution of ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate(0.05 mmol) in THF (0.1M) at 0° C. was added dropwise 2M Lithiumborohydride solution in THF (0.497 mmol). The reaction was allowed toslowly warm to rt and stir for an additional 15 h. The mixture was thencooled to 0° C. and acidified to pH 6 with 3N aqueous HCl. The mixturewas extracted with ethyl acetate and the organic layer washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The solidwas then dissolved in 1 mL of a 1:1 mix of acetonitrile and methanol andwas purified by reverse phase preparatory HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient to 5-95% CH₃CN 0.1% TFA) to yield the title compoundas a white solid. MS (ES) 561.2 (M+H).

Example 64 Preparation ofN-(3-(benzylcarbamoyl)benzyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-64

To a stirred solution of EDC (0.055 mmol), HOBT (0.003 mmol),3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid (0.062 mmol), and TEA (0.109 mmol) in DCM (0.1M) was addedbenzylamine (0.055 mmol). The reaction mixture was stirred for 15 h thenconcentrated in vacuo. The residue was dissolved in 1 mL of 1:1 mix ofacetonitrile and methanol and filtered. The filtrate was purified byreverse phase preparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 5-95% CH₃CN 0.1% TFA) to yield the title compound as a whitesolid. MS (ES) 674.1 (M+H).

Example 65 Preparation of ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylateI-65

Title compound was prepared according to the procedure used in Example56 by substituting3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid for3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid.MS (ES) 631.3 (M+H).

Example 66 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylicacid I-66

Title compound was prepared according to the procedure used in Example57 by substituting ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 603.1 (M+H).

Example 67 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(1-(3-phenoxybenzoyl)piperidin-4-yl)-1H-indole-2-carboxamideI-67 Step A. Preparation of tert-butyl(1-(3-phenoxybenzoyl)piperidin-4-yl)carbamate

To a stirred solution of EDC (0.292 mmol), HOBT (0.0474 mmol),3-phenoxybenzoic acid (0.233 mmol) in DCM (0.1M) and TEA (0.934 mmol)was added tert-butyl piperidin-4-ylcarbamate (0.257 mmol). The reactionmixture was stirred for 15 h then concentrated in vacuo. The residue waspurified by flash column chromatography (Combi-Flash Rf, Hex/EtOAc 0-70%gradient) yield the title compound as a white solid.

Step B. Preparation of (4-aminopiperidin-1-yl)(3-phenoxyphenyl)methanone2,2,2-trifluoroacetate

To a stirred solution of tert-butyl(1-(3-phenoxybenzoyl)piperidin-4-yl)carbamate (0.214 mmol) in DCM (0.2M) was added TFA (0.2 mL). The reaction was allowed to stir for twohours then concentrated to give the title compound. It was directly usedfor subsequent step without further purification.

Step C. Example 67

Title compound was prepared according to the procedure used in Example40 using (4-aminopiperidin-1-yl)(3-phenoxyphenyl)methanone2,2,2-trifluoroacetate. MS (ES) 636.3 (M+H).

Example 68 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-N-(3-(((4-nitrophenyl)sulfonyl)carbamoyl)phenyl)-1H-indole-2-carboxamideI-68

A solution of3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxamido)benzoicacid (12.6 mg, 0.022 mmol), 4-nitrobenzenesulfonamide (5.38 mg, 0.027mmol), EDC (4.68 mg, 0.024 mmol) and DMAP (5.42 mg, 0.044 mmol) in DCM(444 μl) was stirred 5 h at rt. The reaction mixture was concentrated invacuo, and the residue was purified by reverse phase preparatory HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient to 40-85% CH₃CN 0.1% TFA) togive the title compound (8.1 mg) as a yellow solid. MS (ES) 751.90(M+H). MS (ES) 751.90 (M+H).

Example 69 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-N-(4-(((4-nitrophenyl)sulfonyl)carbamoyl)phenyl)-1H-indole-2-carboxamideI-69

The title compound was prepared (11.6 mg, 0.015 mmol) according toprocedures described in Example 70 using4-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(2-methylpyridin-3-yl)-1H-indole-2-carboxamido)benzoicacid (22 mg, 0.039 mmol), 4-nitrobenzenesulfonamide (9.40 mg, 0.046mmol), EDC (8.17 mg, 0.043 mmol) and DMAP (9.46 mg, 0.077 mmol) in DCM(775 μl). MS (ES) 751.90 (M+H).

Example 70 Preparation of3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1-(N-(3-(dimethylamino)propyl)-N′-ethylcarbamimidoyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-70

To a solution of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.111 mmol) in CH₂Cl₂ (2.2 mL) at rt was added methyl3-(aminomethyl)benzoate hydrochloride (0.027 g, 0.133 mmol), EDC (32 mg,0.166 mmol) and DMAP (20 mg, 0.166 mmol). The reaction was stirred for1.5 h at rt then aqueous HCl (1 M) was added to the mixture. The mixturewas extracted with CH₂Cl₂ and concentrated in vacuo. The crude ester wasdissolved in a mixture of THF (1.0 mL)/EtOH (0.5 mL), and 2M LiOH (1.0mL) and stirred for 15 h at rt. The reaction mixture was concentratedand the residue was purified by reverse phase preparatory HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient to 30-65% CH₃CN 0.1% TFA) togive Example 25a and the title compound (5.1 mg) as a side product. MS(ES) 740.1 (M+H).

Example 71 Preparation of4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1H-pyrrole-2-carboxylicacid I-71

A mixture of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (55 mg, 0.118 mmol), methyl4-(aminomethyl)-1H-pyrrole-2-carboxylate hydrochloride (25 mg, 0.130mmol), EDC (24 mg, 0.124 mmol) and DMAP (16 mg, 0.130 mmol) in THF (1.2mL) was stirred at rt for 15 h then aqueous HCl (1 M) was added to themixture. The mixture was extracted with CH₂Cl₂ and concentrated invacuo. The residue was dissolved in a mixture of THF (0.4 mL), EtOH (0.2mL), and 2M LiOH (0.33 mL) and stirred for 45 h at rt. The mixture wasacidified with 1M HCl, extracted with EtOAc, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by reverse phasepreparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 30-90%CH₃CN 0.1% TFA) to give the title compound (40 mg) as an off-whitesolid. MS (ES) 588.1 (M+H).

Example 72 Preparation of3-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-72 Step A. Preparation of methyl3-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate

A mixture of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.20 mmol), methyl 3-(aminomethyl)benzoate hydrochloride(42 mg, 0.21 mmol), EDC (57 mg, 0.30 mmol) and DMAP (37 mg, 0.30 mmol)in THF (2.0 mL) was stirred at rt for 15 h then concentrated in vacuo.The residue was purified by reverse phase preparatory HPLC (PhenomenexGemini C18, H₂O/CH₃CN gradient to 50-95% CH₃CN 0.1% TFA) to give thetitle compound (55 mg) as a white solid. MS (ES) 647.1 (M+H).

Step B. Example 72

A mixture of methyl3-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(40 mg, 0.062 mmol) and 2 M LiOH aqueous solution (0.31 mL, 0.62 mmol)in THF (0.41 mL) and Ethanol (0.21 mL) was stirred for 40 h at rt. Thereaction mixture was acidified with IM HCl, extracted with EtOAc, driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby reverse phase preparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient to 30-95% CH₃CN 0.1% TFA) to give the title compound (31 mg) asa white solid. MS (ES) 633.2 (M+H).

Example 73 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-(piperidin-1-yl)benzoicacid I-73 Step A. Preparation of methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-(piperidin-1-yl)benzoate

The title compound (60 mg) was prepared according to proceduresdescribed in Example 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (82 mg, 0.176 mmol) and methyl5-(aminomethyl)-2-(piperidin-1-yl)benzoate 2,2,2-trifluoroacetate (96mg, 0.264 mmol). MS (ES) 696.3 (M+H).

Step B. Example 73

The title compound (8.1 mg) was prepared according to proceduresdescribed in Example 72 B using methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-(piperidin-1-yl)benzoate(13 mg, 0.019 mmol). MS (ES) 682.2 (M+H).

Example 74 Preparation of4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1-methyl-1H-pyrrole-2-carboxylicacid I-74 Step A. Preparation of methyl4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1-methyl-1H-pyrrole-2-carboxylate

The title compound (22 mg) was prepared according to proceduresdescribed in Example 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.044 mmol) and methyl4-(aminomethyl)-1-methyl-1H-pyrrole-2-carboxylate hydrochloride (9 mg,0.044 mmol).

Step B. Example 74

The title compound (4.5 mg) was prepared according to proceduresdescribed in Example 72 B using methyl4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1-methyl-1H-pyrrole-2-carboxylate(6 mg, 9.74 mol). MS (ES) 602.2 (M+H).

Example 75 Preparation of1-benzyl-4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1H-pyrrole-2-carboxylicacid I-75 Step A. Preparation of methyl1-benzyl-4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1H-pyrrole-2-carboxylate

The title compound (81 mg) was prepared according to proceduresdescribed in Example 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (61 mg, 0.132 mmol) and methyl4-(aminomethyl)-1-benzyl-1H-pyrrole-2-carboxylate hydrochloride (37 mg,0.132 mmol). MS (ES) 692.3 (M+H).

Step B. Example 75

The title compound (8.5 mg) was prepared according to proceduresdescribed in Example 72 B using methyl1-benzyl-4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1H-pyrrole-2-carboxylate(10 mg, 0.014 mmol). MS (ES) 678.2 (M+H).

Example 76 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-(pyrrolidin-1-yl)benzoicacid I-76 Step A. Preparation of methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-(pyrrolidin-1-yl)benzoate

The title compound (56 mg) was prepared according to proceduresdescribed in Example 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (61 mg, 0.132 mmol) and methyl5-(aminomethyl)-2-(pyrrolidin-1-yl)benzoate (31 mg, 0.132 mmol). MS (ES)682.3 (M+H).

Step B. Example 76

The title compound (7.5 mg) was prepared according to proceduresdescribed in Example 72 B using methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-(pyrrolidin-1-yl)benzoate(10 mg, 0.015 mmol). MS (ES) 668.2 (M+H).

Example 77 Preparation of1-benzyl-4-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-1H-pyrrole-2-carboxylicacid I-77

A mixture of methyl1-benzyl-4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1H-pyrrole-2-carboxylate(45 mg, 0.065 mmol), 1,3-dibromopropane (33 μL, 0.325 mmol) and Cs₂CO₃(212 mg, 0.650 mmol) in DMF (0.650 mL) was stirred for 40 h at 100° C.The reaction was quenched with 10% Na₂S₂O₃. The mixture was extractedwith EtOAc and concentrated in vacuo. The crude ester was dissolved inEtOH (2.6 mL), and KOH (365 mg, 0.65 mmol) was added. The reactionmixture was stirred for 15 h at 60° C. then concentrated in vacuo. Theresidue was purified by reverse phase preparatory HPLC (PhenomenexGemini C18, H₂O/CH₃CN gradient to 40-80% CH₃CN 0.1% TFA) to give thetitle compound (20 mg) as a white solid. MS (ES) 718.3 (M+H).

Example 78 Preparation of5-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-2-(pyrrolidin-1-yl)benzoicacid I-78

The title compound was prepared (16 mg) according to proceduresdescribed in Example 77 using methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-(pyrrolidin-1-yl)benzoate(40 mg, 0.059 mmol). MS (ES) 708.3 (M+H).

Example 79 Preparation of4-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-1-methyl-1H-pyrrole-2-carboxylicacid I-79

The title compound was prepared (5.6 mg) according to proceduresdescribed in Example 77 using methyl4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1-methyl-1H-pyrrole-2-carboxylate(10 mg, 0.016 mmol) and 1,3-dibromopropane (8.24 μl, 0.081 mmol). MS(ES) 642.3 (M+H).

Example 80 Preparation of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-80

The title compound was prepared (49 mg), according to proceduresdescribed in Example 77 using methyl3-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(68 mg, 0.105 mmol) and 1,3-dibromopropane (53 μl, 0.525 mmol). MS (ES)673.2 (M+H).

Example 81 Preparation of5-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-2-(piperidin-1-yl)benzoicacid I-81

The title compound was prepared (15 mg) according to proceduresdescribed in Example 77 using methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-(piperidin-1-yl)benzoate(24 mg, 0.034 mmol) and 1,3-dibromopropane (17 μl, 0.17 mmol). MS (ES)722.3 (M+H).

Example 82 Preparation of4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-82 Step A. Preparation of methyl4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate

The title compound (150 mg) was prepared according to proceduresdescribed in Example 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (116 mg, 0.25 mmol) and methyl 4-(aminomethyl)benzoatehydrochloride (50 mg, 0.25 mmol). MS (ES) 613.2 (M+H).

Step B. Example 82

The title compound (22 mg) was prepared according to proceduresdescribed in Example 72 B using methyl4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(30 g, 0.049 mmol). MS (ES) 599.2 (M+H).

Example 83 Preparation of4-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-83

The title compound was prepared (75 mg) according to proceduresdescribed in Example 77 using methyl4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(120 mg, 0.20 mmol) and 1,3-dibromopropane (99 μl, 0.98 mmol). MS (ES)639.3 (M+H).

Example 84 Preparation of3-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-(pyrrolidin-1-yl)benzoicacid I-84 Step A. Preparation of methyl3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-5-(pyrrolidin-1-yl)benzoate

The title compound (50 mg) was prepared according to proceduresdescribed in Example 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (74 mg, 0.159 mmol) and methyl3-(aminomethyl)-5-(pyrrolidin-1-yl)benzoate hydrochloride (56 mg, 0.207mmol).

Step B. Example 84

The title compound was prepared (8 mg) according to procedures describedin Example 77 using methyl3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-5-(pyrrolidin-1-yl)benzoate(15 mg, 0.022 mmol) and (11 μl, 0.11 mmol). MS (ES) 708.3 (M+H).

Example 85 Preparation of2-(3-(1H-tetrazol-5-yl)benzyl)-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneI-85 Step A. Preparation of ethyl1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

To a solution of ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(60 mg, 0.121 mmol) and tert-butyl 1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (33 mg, 0.146 mmol) in DMF (0.4 mL) was added NaH (4.37 mg,0.182 mmol) at rt. The reaction mixture was stirred for 15 h at rt,quenched by addition of H₂O extracted with EtOAc. The combined organiclayer was washed with H₂O followed by brine, dried over MgSO₄, filteredand concentrated in vacuo. The crude product was directly used for thenext step without further purification. MS (ES) 637.2 (M+H).

Step B. Preparation of10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one

A mixture of ethyl1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(64 mg, 0.101 mmol) and TFA (0.2 ml, 2.53 mmol) in CH₂Cl₂ (0.45 mL) wasstirred at rt for 30 min then concentrated in vacuo. The residue wasdissolved in MeOH (0.4 mL), and K2CO₃ (49 mg, 0.35 mmol) was added atrt. The reaction mixture was stirred at 50° C. for 90 h. The reactionmixture was filtered through a hydrophobic fit and concebtrated. Theresidue was purified by reverse phase preparatory HPLC (PhenomenexGemini C18, H₂O/CH₃CN gradient to 40-80% CH₃CN 0.1% TFA) to give thetitle compound (35 mg) as a white solid. SMS (ES) 491.1 (M+H).

Step C. Preparation of3-((10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzonitrile

A mixture of10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one(21 mg, 0.043 mmol) and NaH (2.1 mg, 0.086 mmol) in DMF (0.43 ml) wasstirred at 0° C. After 30 min, 3-(bromomethyl)benzonitrile (17 mg, 0.086mmol) was added to the mixture. The mixture was then warmed to rt andstirred for additional 1 h. The mixture was quenched with sat. NH₄Claqueous solution, extracted with Et₂O, dried over Na₂SO₄, filtered andconcentrated in vacuo to give the tile compound, which was used directlywithout further purification. MS (ES) 606.1 (M+H).

Step D. Example 85

A mixture of3-((10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzonitrile(26 mg, 0.043 mmol), sodium azide (17 mg, 0.26 mmol) and NH₄Cl (14 mg,0.26 mmol) in DMF (0.15 mL) was stirred at 120° C. for 15 h.

The cooled reaction mixture was filtered and purified by reverse phasepreparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 40-80%CH₃CN 0.1% TFA) to give the title compound (15 mg) as a white solid. MS(ES) 649.3 (M+H).

Example 86 Preparation of3-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-nitrobenzoicacid I-86 Step A. Preparation of methyl3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-5-nitrobenzoate

The title compound (119 mg) was prepared according to proceduresdescribed in Example 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.22 mmol) and methyl 3-(aminomethyl)-5-nitrobenzoate2,2,2-trifluoroacetate (104 mg, 0.322 mmol). MS (ES) 658.2 (M+H).

Step B. Example 86

The title compound was prepared (18 mg) according to proceduresdescribed in Example 77 using methyl3-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-5-nitrobenzoate(59 mg, 0.090 mmol) and 1,3-dibromopropane (45 μA, 0.045 mmol). MS (ES)684.2 (M+H).

Example 87 Preparation of4-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-87 Step A. Preparation of methyl4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate

The title compound was prepared according to procedures described inExample 72 A using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (75 mg, 0.15 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride(32 mg, 0.16 mmol). MS (ES) 647.2 (M+H).

Step B. Example 87

The title compound was prepared (55 mg) according to proceduresdescribed in Example 77 using methyl4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(0.15 mmol) and 1,3-dibromopropane (76 μL, 0.75 mmol). MS (ES) 673.2(M+H).

Example 88 Preparation of2-(4-(1H-tetrazol-5-yl)benzyl)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-88 Step A. Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(4-cyanobenzyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide

The title compound was prepared according to procedures described inExample 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (75 mg, 0.161 mmol) and 4-(aminomethyl)benzonitrile hydrochloride(28 mg, 0.169 mmol). MS (ES) 580.2 (M+H).

Step B. Preparation of4-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzonitrile

The title compound was prepared according to procedures described inExample 77 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(4-cyanobenzyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide(0.093 g, 0.161 mmol) and 1,3-dibromopropane (82 μL, 0.81 mmol). MS (ES)620.2 (M+H).

Step B. Example 88

The title compound was prepared (45 mg) according to proceduresdescribed in Example 85 Step D using of4-((11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzonitrile(100 mg, 0.16 mmol), sodium azide (63 mg, 0.97 mmol) and ammoniumchloride (52 mg, 0.97 mmol). MS (ES) 663.3 (M+H).

Example 89 Preparation of2-(2-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1H-pyrrol-1-yl)aceticacid I-89 Step A. Preparation of methyl2-(2-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1H-pyrrol-1-yl)acetate

The title compound (74 mg) was prepared according to proceduresdescribed in Example 72 A using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (58 mg, 0.13 mmol) and methyl2-(2-(aminomethyl)-1H-pyrrol-1-yl)acetate (0.034 g, 0.20 mmol). MS (ES)616.3 (M+H).

Step B. Example 89

The title compound (65 mg) was prepared according to proceduresdescribed in Example 72 B using methyl2-(2-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-1H-pyrrol-1-yl)acetate(74 mg, 0.12 mmol). MS (ES) 602.2 (M+H).

Example 90 Preparation of4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-(4-methylpiperazin-1-yl)benzoicacid I-90 Step A. Preparation of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride

To a solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (275 mg, 0.550 mmol) in CH₂Cl₂ (11 mL) was added oxalyl chloride(0.2 mL, 2.2 mmol) and DMF (2.1 μL, 0.028 mmol) rt. The reaction mixturewas stirred at rt for 3 h then concentrated in vacuo to give the crudetitle compound, which was used in subsequent reactions without furtherpurification.

Step B. Preparation of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-(4-methylpiperazin-1-yl)benzoate

A mixture of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (83 mg, 0.16 mmol), methyl4-amino-2-(4-methylpiperazin-1-yl)benzoate (40 mg, 0.16 mmol) and DIPEA(84 μl, 0.481 mmol) in CH₂Cl₂ (3.2 mL) was stirred at rt for 4 h thenconcentrated in vacuo. The residue was purified by reverse phasepreparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to 30-95%CH₃CN 0.1% TFA) to give the title compound (55 mg) as a white solid. MS(ES) 731.3 (M+H).

Step C. Example 90

A mixture of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-(4-methylpiperazin-1-yl)benzoate(55 mg, 0.075 mmol) and 2M LiOH (400 μL, 0.80 mmol) in THF (2.0 mL) wasstirred at 50° C. for 3 h. The reaction mixture was acidified with 1MHCl, extracted with EtOAc, dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by reverse phase preparatory HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient to 15-95% CH₃CN 0.1% NH₄₀OH)to give the title compound (35 mg) as a white solid. MS (ES) 717.3(M+H).

Example 91 Preparation of4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-morpholinobenzoicacid I-91 Step A. Preparation of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-morpholinobenzoate

The title compound (24 mg) was prepared according to proceduresdescribed in Example 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (35 mg, 0.068 mmol) and methyl 4-amino-2-morpholinobenzoate (16mg, 0.068 mmol). MS (ES) 718.2 (M+H).

Step B. Example 91

The title compound (18 mg) was prepared according to proceduresdescribed in Example 90 C using methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-morpholinobenzoate(24 mg, 0.033 mmol). MS (ES) 704.2 (M+H).

Example 92 Preparation of4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoicacid I-92 Step A. Preparation of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoate

The title compound (50 mg) was prepared according to proceduresdescribed in Example 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (51 mg, 0.099 mmol) and methyl4-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoate (25 mg, 0.099mmol). MS (ES) 733.3 (M+H).

Step B. Example 92

The title compound (41 mg) was prepared according to proceduresdescribed in Example 90 C using methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoate(45 mg, 0.061 mmol). MS (ES) 719.3 (M+H).

Example 93 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-2-(trifluoromethyl)benzoicacid I-93 Step A. Preparation of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-(trifluoromethyl)benzoate

The title compound (49 mg) was prepared according to proceduresdescribed in Example 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (52 mg, 0.10 mmol) and methyl4-amino-2-(trifluoromethyl)benzoate (22 mg, 0.10 mmol). MS (ES) 700.2(M+H).

Step B. Example 93

A mixture of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-(trifluoromethyl)benzoate(20 mg, 0.029 mmol), 1,3-dibromopropane (7.2 μL, 0.071 mmol) and Cs₂CO₃(46 mg, 0.14 mmol) in DMF (0.57 mL) was stirred for 15 h at 80° C. Thereaction was quenched with 10% Na₂S₂O₃. The mixture was extracted withEtOAc and concentrated in vacuo. The crude ester was dissolved in THF(0.30 mL), and 2M LiOH aqueous solution (73 μL, 0.15 mmol) was added.The reaction mixture was stirred for 3 h at 50° C. then concentrated invacuo. The residue was purified by reverse phase preparatory HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient to 45-95% CH₃CN 0.1% TFA) togive the title compound (8 mg) as a white solid. MS (ES) 727.2 (M+H).

Example 94 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-2-fluorobenzoicacid I-94 Step A. Preparation of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-fluorobenzoate

The title compound (45 mg) was prepared according to proceduresdescribed in Example 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (52 mg, 0.10 mmol) and methyl 4-amino-2-fluorobenzoate (17 mg,0.10 mmol). MS (ES) 651.2 (M+H).

Step B. Example 94

The title compound (14 mg) was prepared according to proceduresdescribed in Example 93 B using methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-fluorobenzoate(25 mg, 0.038 mmol) and 1,3-dibromopropane (9.7 μL, 0.096 mmol). MS (ES)677.2 (M+H).

Example 95 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-3-fluorobenzoicacid I-95 Step A. Preparation of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-3-fluorobenzoate

The title compound (35 mg) was prepared according to proceduresdescribed in Example 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (52 mg, 0.10 mmol) and methyl 4-amino-3-fluorobenzoate (17 mg,0.10 mmol). MS (ES) 651.2 (M+H).

Step B. Example 95

The title compound (17 mg) was prepared according to proceduresdescribed in Example 93 B using methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-3-fluorobenzoate(25 mg, 0.038 mmol) and 1,3-dibromopropane (9.7 μL, 0.096 mmol). MS (ES)677.2 (M+H).

Example 96 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-2-methylbenzoicacid I-96 Step A. Preparation of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-methylbenzoate

The title compound (60 mg) was prepared according to proceduresdescribed in Example 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (52 mg, 0.10 mmol) and methyl 3-amino-4-methylbenzoate (18 mg,0.11 mmol). MS (ES) 647.2 (M+H).

Step B. Example 96

The title compound (31 mg) was prepared according to proceduresdescribed in Example 93 B using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-methylbenzoate(60 mg, 0.092 mmol) and 1,3-dibromopropane (25.4 μL, 0.250 mmol). MS(ES) 673.2 (M+H).

Example 97 Preparation of4-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-3-methylbenzoicacid I-97 Step A. Preparation of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-3-methylbenzoate

The title compound (55 mg) was prepared according to proceduresdescribed in Example 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (52 mg, 0.10 mmol) and methyl 4-amino-3-methylbenzoate (18 mg,0.11 mmol). MS (ES) 647.2 (M+H).

Step B. Example 97

The title compound (27 mg) was prepared according to proceduresdescribed in Example 93 B using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-methylbenzoate(55 mg, 0.092 mmol) and 1,3-dibromopropane (25 μL, 0.25 mmol). MS (ES)673.2 (M+H).

Example 98 Preparation of5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-2-methylbenzoicacid I-98 Step A. Preparation of methyl5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-methylbenzoate

The title compound was prepared according to procedures described inExample 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (50 mg, 0.10 mmol) and methyl 5-amino-2-methylbenzoate (18 mg,0.11 mmol). MS (ES) 647.2 (M+H).

Step B. Example 98

The title compound (33 mg) was prepared according to proceduresdescribed in Example 93 B using methyl5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-methylbenzoate(64 mg, 0.10 mmol) and 1,3-dibromopropane (25 μL, 0.25 mmol). MS (ES)673.2 (M+H).

Example 99 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-2-methylbenzoicacid I-99 Step A. Preparation of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-methylbenzoate

The title compound was prepared according to procedures described inExample 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (52 mg, 0.10 mmol) and methyl 4-amino-2-methylbenzoate (18 mg,0.11 mmol). MS (ES) 647.2 (M+H).

Step B. Example 99

The title compound (29 mg) was prepared according to proceduresdescribed in Example 93 B using methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-2-methylbenzoate(64 mg, 0.10 mmol) and 1,3-dibromopropane (25 μL, 0.25 mmol). MS (ES)673.2 (M+H).

Example 100 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-4-methylbenzoicacid I-100 Step A. Preparation of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-4-methylbenzoate

The title compound was prepared according to procedures described inExample 90 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (52 mg, 0.10 mmol) and methyl 3-amino-4-methylbenzoate (18 mg,0.11 mmol). MS (ES) 647.2 (M+H).

Step B. Example 100

The title compound (39 mg) was prepared according to proceduresdescribed in Example 93 B using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-4-methylbenzoate(64 mg, 0.10 mmol) and 1,3-dibromopropane (25 μL, 0.25 mmol). MS (ES)673.2 (M+H).

Example 101 Preparation of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(3-(trifluoromethoxy)phenyl)-7-((1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-101 Step A. Preparation of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(trifluoromethoxy)phenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide

The title compound was prepared according to procedures described inExample 72 A using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.10 mmol) and 3-(trifluoromethoxy)aniline (16 μL, 0.12mmol). MS (ES) 659.2 (M+H).

Step B. Example 101

The title compound (46 mg) was prepared according to proceduresdescribed in Example 93 B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(trifluoromethoxy)phenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide(66 mg, 0.10 mmol) and 1,3-dibromopropane (25 μL, 0.25 mmol). MS (ES)673.2 (M+H).

Example 102 Preparation of6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)nicotinicacid I-102 Step A. Preparation of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one

The title compound was prepared according to procedures described inExample 85 A and B using ethyl3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand substituting tert-butyl 1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide with tert-butyl 1,2,3-oxathiazinane-3-carboxylate2,2-dioxide in 75% yield.

Step B. Preparation of methyl6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)nicotinate

To a solution of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(20 mg, 0.037 mmol) in DMF (1 mL) was added a mixture of NaH (1.8 mg,0.045 mmol) and catalytic amount of TBAI, followed by addition of methyl6-(bromomethyl)nicotinate (14 mg, 0.063 mmol) at 0° C. The reactionmixture was stirred for 2 h at room temperature and diluted with EtOAc(5 mL) then quenched with water (3 mL). The organic layer was washedwith water (3×5 mL), dried over MgSO₄, and concentrated in vacuo to givethe crude title product, which was used to next step without furtherpurification.

Step C. Example 102

To a solution of methyl6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)nicotinate (crude, 0.037 mmol) in mixture of MeOH and dioxane (1 mL/2mL) was added sodium hydroxide (0.2 mL, 2M solution). The reactionmixture was stirred for 3 h at rt, acidified with 1N HCl (2 mL), andthen concentrated in vacuo. The residue was purified by columnchromatography using DCM/MeOH (Combi-flash Rf, 0 to 30% MeOH gradient)to afford the title compound as a yellow solid (14 mg, 57%). ¹H NMR(MeOD, 400 MHz) δ (ppm) 9.06 (s, 1H), 8.29 (dd, J=8.0, 1.6 Hz, 1H), 7.68(d, J=8.8 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.66(s, 2H), 4.82 (d, J=3.6 Hz, 2H), 3.93 (t, J=6.0 Hz, 4H), 3.83 (s, 3H),3.19 (t, J=7.2 Hz, 2H), 2.38-2.25 (m, 2H), 2.31 (s, 6H), 2.16 (q, J=6.4Hz, 1H), 2.06 (s, 3H), 1.97 (s, 3H), 1.75-1.63 (m, 2H); LCMS (ES) tR:0.776 min (>99%, ELSD), 674.2 [M+1]

Example 103 Preparation of5-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)furan-2-carboxylicacid I-103

The title compound was prepared according to procedures described inExample 102 B and C using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 5-(chloromethyl)furan-2-carboxylate; ¹H NMR (MeOD, 400 MHz) δ(ppm) 7.67 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.99 (d, J=3.2 Hz,1H), 6.66 (s, 2H), 6.44 (d, J=3.6 Hz, 1H), 4.62 (s, 2H), 3.90 (t, J=6.0Hz, 2H), 3.83 (s, 3H), 3.82-3.80 (m, 2H), 3.29 (t, J=6.4 Hz, 2H), 3.18(t, J=7.2 Hz, 2H), 2.32 (s, 6H), 2.17-2.13 (m, 2H), 2.04 (s, 3H), 1.95(s, 3H), 1.58-1.53 (m, 2H); LCMS (ES) tR: 0.796 min (>99%, ELSD), 663.2[M+1]

Example 104 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)quinoline-8-carboxylicacid I-104 Step A. Preparation of methyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)quinoline-8-carboxylate

A flame dried flask was charged with Pd₂(dba)₃ (1 mg, 0.5 mol %),Xantphos (2 mg, 1 mol %), cesium carbonate (27 mg, 0.084 mmol),8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(30 mg, 0.056 mmol), methyl 4-bromoquinoline-8-carboxylate (18 mg, 0.067mmol), and 1,4-dioxane (1 mL). The reaction mixture was degassed for 10min under argon and stirred for 16 h at 110° C. then solvent wasconcentrated in vacuo. The residue was filtered through celite pad withMeOH then solvent was removed in vacuo to give the crude title compoundwhich was used in the next reaction without further purification.

Step B. Example 104

To a solution of methyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)quinoline-8-carboxylate(crude, 0.056 mmol) in mixture of methanol and dioxane (1 mL/2 mL) wasadded sodium hydroxide (0.2 mL, 2M solution). The reaction mixture wasstirred for 3 h at room temperature and then concentrated in vacuo. Theresidue was purified by reverse phase preparatory HPLC (PhenomenexGemini C18, H₂O/CH₃CN gradient to 45-95% CH₃CN 0.1% TFA) to give thetitle compound (22 mg, 58%) as a yellow solid. ¹H NMR (DMSO-d⁶, 400 MHz)δ (ppm) 9.17 (d, J=4.8 Hz, 1H), 8.59 (d, J=7.6 Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.79 (dd, J=12.8, 8.0 Hz, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.28 (d,J=8.4 Hz, 1H), 6.70 (s, 2H), 4.20 (t, J=6.0 Hz, 2H), 3.96 (t, J=6.0 Hz,2H), 3.77 (s, 3H), 3.75-3.50 (m, 2H), 3.04 (t, J=7.2 Hz, 2H), 2.22 (s,6H), 2.20-2.05 (m, 2H), 2.04 (s, 3H), 1.93 (s, 3H), 1.87-1.73 (m, 2H);LCMS (ES) tR: 1.392 min (>99%, ELSD), 711.2 [M+1].

Example 105 Preparation of4-(11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)quinoline-8-carboxylicacid I-105

The title compound was prepared according to procedures described inExample 104 Step A and B using11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand 4-bromoquinoline-8-carboxylate; ¹H NMR (DMSO, 400 MHz) δ (ppm) 9.17(d, J=5.2 Hz, 1H), 8.59 (d, J=6.8 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.79(dd, J=12.4, 7.6 Hz, 2H), 7.72 (d, J=8.0 Hz, 1H), 7.14 (t, J=7.6 Hz,1H), 6.97 (d, J=7.6 Hz, 1H), 6.71 (s, 2H), 4.29 (t, J=6.0 Hz, 2H), 3.97(t, J=6.4 Hz, 2H), 3.75 (s, 3H), 3.74-3.67 (m, 2H), 3.06 (t, J=7.2 Hz,2H), 2.26 (s, 6H), 2.15-2.01 (m, 2H), 2.05 (s, 3H), 1.95 (s, 3H),1.88-1.78 (m, 2H); LCMS (ES) tR: 1.318 min (>99%, ELSD), m/z: 677.1[M+1].

Example 106 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-7-carboxylicacid I-106

The title compound was prepared according to procedures described inExample 104 A and B using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 4-bromo-1-methyl-3a,7a-dihydro-1H-indole-7-carboxylate; ¹HNMR (DMSO, 400 MHz) δ (ppm) 7.70 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz,1H), 7.36 (d, J=3.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.0 Hz,1H), 6.70 (s, 2H), 6.36 (d, J=3.2 Hz, 1H), 4.09 (t, J=6.4 Hz, 2H), 3.95(t, J=6.4 Hz, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 3.65 (t, J=6.0 Hz, 2H),3.03 (t, J=6.8 Hz, 2H), 2.23 (s, 6H), 2.09-2.03 (m, 2H), 2.01 (s, 3H),1.91 (s, 3H), 1.79-1.70 (m, 2H); LCMS (ES) tR: 1.515 min (>99%, ELSD),m/z: 713.2 [M+1].

Example 107 Preparation of5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)quinoline-8-carboxylicacid I-107

The title compound was prepared according to procedures described inExample 104 A and B using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 5-bromoquinoline-8-carboxylate; ¹H NMR (DMSO, 400 MHz) δ(ppm) 9.15 (d, J=4.4 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.54 (d, J=8.0 Hz,1H), 7.80-7.72 (m, 3H), 7.28 (d, J=8.4 Hz, 1H), 6.70 (s, 2H), 4.20 (t,J=6.0 Hz, 2H), 3.96 (t, J=6.0 Hz, 2H), 3.77 (s, 3H), 3.75-3.50 (m, 2H),3.03 (t, J=6.4 Hz, 2H), 2.22 (s, 6H), 2.12-2.05 (m, 2H), 2.05 (s, 3H),1.94 (s, 3H), 1.89-1.69 (m, 2H); LCMS (ES) tR: 1.377 min (>99%, ELSD),m/z: 711.1 [M+1].

Example 108 Preparation of8-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)quinoline-5-carboxylicacid I-108

The title compound was prepared according to procedures described inExample 104 A and B using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 8-bromoquinoline-5-carboxylate; ¹H NMR (DMSO, 400 MHz) δ(ppm) 9.32 (dd, J=8.8, 1.6 Hz, 1H), 8.90 (dd, J=4.0, 1.6 Hz, 1H), 8.25(d, J=7.6 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.8, 3.6 Hz, 2H),7.25 (d, J=8.4 Hz, 1H), 6.72 (s, 2H), 4.33 (t, J=6.4 Hz, 2H), 3.94 (t,J=6.4 Hz, 2H), 3.76 (s, 3H), 3.71 (t, J=6.4 Hz, 2H), 3.02 (t, J=6.8 Hz,2H), 2.22 (s, 6H), 2.06 (t, J=6.8 Hz, 2H), 2.03 (s, 3H), 1.92 (s, 3H),1.80-1.68 (m, 2H); LCMS (ES) tR: 1.380 min (>99%, ELSD), m/z: 711.1[M+1].

Example 109 Preparation of(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneI-109 Step A. Preparation of ethyl(R)-1-(2-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

To a flame dried round bottom flask (50 mL) equipped with magnetic stirbar was added ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(360 mg, 0.683 mol) and anhydrous DMF (2 mL) and the solution wasstirred in ice bath under nitrogen atmosphere. Sodium hydride (60%) (25mg, 0.62 mol) was added and after 3 min tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was added.The reaction mixture was stirred in the ice bath for 20 min and then atrt for overnight. The reaction mixture was diluted with ethyl acetate(50 mL) and washed with brine (2×30 mL), dried with anhydrous MgSO₄,filtered off and concentrated down using rotary evaporator. The residuewas purified by flash chromatography (Combi-flash Rf, Hex/acetone 80/20)to give the title compound (305 mg, 65%). ¹H NMR (CDCl₃) δ 7.66 (d, 1H,J=8 Hz), 7.32 (d, 1H, J=8 Hz), 6.65 (s, 2H), 4.30 (q, 2H, J 1=8 Hz),4.20 (m, 2H), 4.03 (t, 2H, J=8 Hz), 3.87 (s, 3H), 3.39-3.30 (m, 4H),3.09 (m, 2H), 2.35 (two s, 6H), 2.09-2.00 (m, 2H), 1.45 (s, 9H),1.29-1.18 (multiple d, total 3H), 0.99 (tr, 3H, J=8 Hz). MS (ES) 686.3(M+H).

Step B. Example 109

The solution of ethyl(R)-1-(2-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(218 mg, 0.32 mol) in anhydrous CH₂Cl₂ was cooled at 0° C. in ice bath.TFA (1.5 mL) was added dropwise, and the reaction mixture was stirred atrt for 2 h. The solvent was removed in vacuo and anhydrous ethanol (10mL) was added followed by anhydrous K2CO₃ (829 mg, 1.92 mmols). Thereaction mixture was stirred at rt for overnight. The reaction mixturewas diluted with ethyl acetate (60 mL) and washed with brine (2×30 mL).The organic layers were dried with anhydrous MgSO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(Combi-flash Rf, CH₂Cl₂/methanol=0-10% gradient) to give the titlecompound (150 mg, 87%). ¹H NMR (CDCl₃) δ 7.64 (d, 1H, J=8 Hz), 7.31 (d,1H, J=8 Hz), 6.65 (s, 2H), 5.63 (d, 1H, J=12 Hz), 4.03 (t, 2H, J=8 Hz),3.87 (s, 3H), 3.85-3.73 (m, 2H), 3.39-3.30 (m, 2H), 2.35 (s, 6H), 2.25(tr, 2H, J=8 Hz), 2.07-2.05 (s, 6H), 1.18 (m, 3H). MS (ES) 539.5 (M+H).

Example 110 Preparation of(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneI-110

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide. MS (ES) 539.2 (M+H)

Example 111 Preparation of7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneI-111

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.MS (ES) 539.2 (M+H)

Example 112 Preparation of(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneI-112

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl (R)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide. MS (ES) 539.2 (M+H)

Example 113 Preparation of(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneI-113

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide. MS (ES) 539.2 (M+H).

Example 114 Preparation of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-114

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl 4-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide.MS (ES) 553.2 (M+H).

Example 115 Preparation of8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-115

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl 5-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide.MS (ES) 553.2 (M+H).

Example 116 Preparation of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-5-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-116

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide.MS (ES) 553.2 (M+H).

Example 117 Preparation of7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneI-117

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. MS (ES)525.2 (M+H).

Example 118 Preparation of8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-118

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide. MS (ES)539.2 (M+H).

Example 119 Preparation of(3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneI-119

The title compound was prepared according to procedures described inExample 109 A and B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylateand tert-butyl (4R)-4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide. MS (ES) 553.2 (M+H).

Example 120 Preparation of(R)-4-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-120

To a flame dried round bottom flask (25 mL) equipped with magnetic stirbar was added(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 46.3 mmol) and anhydrous DMF (2 mL) and the solutionwas stirred in ice bath under nitrogen atmosphere. Sodium hydride (60%)(5.5 mg, 78.7 mmol) was added to the reaction mixture and stirred for 10min. Methyl 4-(bromomethyl)benzoate (1.7 eq) was added to the reactionmixture then stirred in the ice bath for 10 min. The reaction mixturewas warmed to rt, stirred for additional 1 h then diluted with ethylacetate (20 mL). The organic solution was washed with brine (2×10 mL),dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Theresidue was dissolved in a mixture of THF and MeOH (4 mL, 1:1) and NaOH(2M, 1 mL) aqueous solution was added. The reaction was stirred at rtwhile monitoring progress by LCMS until completion. The reaction mixturewas acidified with HCl (1.2 M), concentrated to ½ of its originalvolume, diluted with ethyl acetate and washed with water. The organiclayer was concentrated in vacuo. The residue was purified by reversephase preparatory HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient to50-95% CH₃CN 0.1% TFA) to give the title compound (22 mg, 58%) as ayellow solid down using rotary evaporator and dissolved in a mixture ofDMSO and MEOH and purified by HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient 50-95% CH₃CN, 0.1% TFA) to give the title compound (81% yield)as a white solid. ¹H NMR (CDCl₃) δ 8.04 (d, 2H, J=8 Hz), 7.70-7.67 (m,1H), 7.14 (m, 2H), 7.31 (m, 1H), 6.67 (s, 2H), 5.59 (tr, 1H, J=16 Hz),4.04-4.00 (m, 4H), 3.93 and 3.89 (s, 3H), 3.64-3.37 (m, 4H), 2.35 (s,6H), 2.25 (m, 2H), 2.07-2.05 (s, 6H), 1.13 and 1.08 (d, 3H, J=8 Hz). MS(ES) 673.2 (M+H).

Example 121 Preparation of(R)-3-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-121

The title compound was prepared according to procedures described inExample 120 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 3-(bromomethyl)benzoate (68% yield). ¹H NMR (CDCl₃) δ 8.02(m, 2H), 7.68 (d, 1H, J=8 Hz), 7.59 (m, 1H), 7.48 (m, 1H), 7.27 (m, 1H),6.67 (s, 2H), 5.55 (m, 1H), 4.04 (m, 4H), 3.99 and 3.89 (s, 3H),3.60-3.55 (m, 2H), 3.45-3.37 (m, 2H), 2.35 (s, 6H), 2.25 (m, 2H),2.07-2.05 (multiple s, 6H), 1.12 and 1.08 (d, 3H, J=8 Hz). MS (ES) 673.2(M+H).

Example 122 Preparation of(R)-6-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)nicotinicacid I-122

The title compound was prepared according to procedures described inExample 120 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 3-(bromomethyl)benzoate (68% yield). ¹H NMR (CDCl₃) δ 8.02(m, 2H), 7.68 (d, 1H, J=8 Hz), 7.59 (m, 1H), 7.48 (m, 1H), 7.27 (m, 1H),6.67 (s, 2H), 5.55 (m, 1H), 4.04 (m, 4H), 3.99 and 3.89 (s, 3H),3.60-3.55 (m, 2H), 3.45-3.37 (m, 2H), 2.35 (s, 6H), 2.25 (m, 2H),2.07-2.05 (multiple s, 6H), 1.12 and 1.08 (d, 3H, J=8 Hz). MS (ES) 673.2(M+H).

Example 123 Preparation of(R)-5-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)furan-2-carboxylicacid I-123

The title compound was prepared according to procedures described inExample 120 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-(bromomethyl)furan-2-carboxylate (78% yield). ¹HNMR (CDCl₃) δ 7.67 (d, 1H, J=8 Hz), 7.27-7.15 (m, 2H), 6.56 (s, 2H),6.49 (d, 1H, J=3 Hz) 5.43 and 5.26 (dd, 1H, J₁=16 Hz, J₂=60 Hz), 4.31and 4.15 (dd, 1H, J₁=16 Hz, J₂=60 Hz), 4.04-3.73 (m, 7H), 3.73-3.54 (m,2H), 3.35-3.24 (m, 2H), 2.25 (s, 6H), 2.18-2.10 (m, 2H), 2.07-2.05(multiple s, 3H), 1.08 and 1.03 (d, 3H, J=8 Hz). MS (ES) 663.2 (M+H).

Example 124-155 was prepared in parallel manner with 47-88% yield.

Example 124 Preparation of6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)nicotinicacid I-124

The title compound was prepared according to procedures described inExample 120 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 6-(bromomethyl)nicotinate. MS (ES) 688.2 (M+H).

Example 125 Preparation of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-125

The title compound was prepared according to procedures described inExample 120 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 3-(bromomethyl)benzoate. MS (ES) 687.2 (M+H).

Example 126 Preparation of5-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)furan-2-carboxylicacid I-126

The title compound was prepared according to procedures described inExample 120 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 5-(bromomethyl)furan-2-carboxylate. MS (ES) 677.2 (M+H).

Example 127 Preparation of4-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-127

The title compound was prepared according to procedures described inExample 120 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 4-(bromomethyl)benzoate. MS (ES) 687.2 (M+H).

Example 128 Preparation of5-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)furan-2-carboxylicacid I-128

The title compound was prepared according to procedures described inExample 120 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 5-(bromomethyl)furan-2-carboxylate. MS (ES) 663.2 (M+H).

Example 129 Preparation of6-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)nicotinicacid I-129

The title compound was prepared according to procedures described inExample 120 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-(bromomethyl)nicotinate. MS (ES) 674.2 (M+H).

Example 130 Preparation of4-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-130

The title compound was prepared according to procedures described inExample 120 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-(bromomethyl)benzoate. MS (ES) 673.2 (M+H).

Example 131 Preparation of3-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-131

The title compound was prepared according to procedures described inExample 120 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-(bromomethyl)benzoate. MS (ES) 673.2 (M+H).

Example 132 Preparation of5-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)furan-2-carboxylicacid I-132

The title compound was prepared according to procedures described inExample 120 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 5-(bromomethyl)furan-2-carboxylate. MS (ES) 677.2 (M+H).

Example 133 Preparation of4-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-133

The title compound was prepared according to procedures described inExample 120 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 4-(bromomethyl)benzoate. MS (ES) 687.2 (M+H).

Example 134 Preparation of6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)nicotinicacid I-134

The title compound was prepared according to procedures described inExample 120 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 6-(bromomethyl)nicotinate. MS (ES) 688.2 (M+H).

Example 135 Preparation of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-135

The title compound was prepared according to procedures described inExample 120 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneand methyl 3-(bromomethyl)benzoate. MS (ES) 687.2 (M+H).

Example 136 Preparation of(S)-3-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-136

The title compound was prepared according to procedures described inExample 120 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-(bromomethyl)benzoate. MS (ES) 673.2 (M+H).

Example 137 Preparation of(S)-6-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)nicotinicacid I-137

The title compound was prepared according to procedures described inExample 120 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 6-(bromomethyl)nicotinate. MS (ES) 674.2 (M+H).

Example 138 Preparation of(S)-5-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)furan-2-carboxylicacid I-138

The title compound was prepared according to procedures described inExample 120 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-(bromomethyl)furan-2-carboxylate. MS (ES) 663.2(M+H).

Example 139 Preparation of(S)-4-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-139

The title compound was prepared according to procedures described inExample 120 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-(bromomethyl)benzoate. MS (ES) 673.2 (M+H).

Example 140 Preparation of4-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-140

The title compound was prepared according to procedures described inExample 120 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 4-(bromomethyl)benzoate. MS (ES) 659.2 (M+H).

Example 141 Preparation of3-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-141

The title compound was prepared according to procedures described inExample 120 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-(bromomethyl)benzoate. MS (ES) 659.2 (M+H).

Example 142 Preparation of6-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)nicotinicacid I-142

The title compound was prepared according to procedures described inExample 120 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 6-(bromomethyl)nicotinate. MS (ES) 660.2 (M+H).

Example 143 Preparation of5-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)furan-2-carboxylicacid I-143

The title compound was prepared according to procedures described inExample 120 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 5-(bromomethyl)furan-2-carboxylate. MS (ES) 649.2 (M+H).

Example 144 Preparation of4-(((3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-144

The title compound was prepared according to procedures described inExample 120 using(3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-(bromomethyl)benzoate. MS (ES) 687.2 (M+H).

Example 145 Preparation of3-(((3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-145

The title compound was prepared according to procedures described inExample 120 using(3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 3-(bromomethyl)benzoate. MS (ES) 687.2 (M+H).

Example 146 Preparation of6-(((3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)nicotinicacid I-146

The title compound was prepared according to procedures described inExample 120 using(3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 6-(bromomethyl)nicotinate. MS (ES) 688.2 (M+H).

Example 147 Preparation of5-(((3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)furan-2-carboxylicacid I-147

The title compound was prepared according to procedures described inExample 120 using(3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-(bromomethyl)furan-2-carboxylate. MS (ES) 677.2(M+H).

Example 148 Preparation of(S)-5-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)furan-2-carboxylicacid I-148

The title compound was prepared according to procedures described inExample 120 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 5-(bromomethyl)furan-2-carboxylate. MS (ES) 663.2 (M+H).

Example 149 Preparation of(S)-6-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)nicotinicacid I-149

The title compound was prepared according to procedures described inExample 120 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-(bromomethyl)nicotinate. MS (ES) 674.2 (M+H).

Example 150 Preparation of(S)-4-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-150

The title compound was prepared according to procedures described inExample 120 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 4-(bromomethyl)benzoate. MS (ES) 673.2 (M+H).

Example 151 Preparation of(S)-3-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-151

The title compound was prepared according to procedures described inExample 120 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 3-(bromomethyl)benzoate. MS (ES) 673.2 (M+H).

Example 152 Preparation of(R)-5-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)furan-2-carboxylicacid I-152

The title compound was prepared according to procedures described inExample 120 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-(bromomethyl)furan-2-carboxylate. MS (ES) 663.2(M+H).

Example 153 Preparation of(R)-6-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)nicotinicacid I-153

The title compound was prepared according to procedures described inExample 120 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-(bromomethyl)nicotinate. MS (ES) 674.2 (M+H).

Example 154 Preparation of(R)-4-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-154

The title compound was prepared according to procedures described inExample 120 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-(bromomethyl)benzoate. MS (ES) 673.2 (M+H).

Example 155 Preparation of(R)-3-((7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)benzoicacid I-155

The title compound was prepared according to procedures described inExample 120 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-(bromomethyl)benzoate. MS (ES) 673.2 (M+H).

Example 156 Preparation of(R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzoicacid I-156

To a flame dried round bottom flask (25 mL) equipped with magnetic stirbar was added(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (25 mg, 46.3 mmol) and anhydrous 1,4-dioxane (2 mL).Sequentially, Cs₂CO₃ (28 mg, 83.7 mmol), Pd₂(dba)₃ (1 mg, 1.1 mmol),Xanthpos (2 mg, 3.3 mmol) and methyl 4-bromobenzoate (1.2 eq) wereadded. The reaction mixture was stirred at 120° C. for overnight. Thereaction mixture concentrated in vacuo and the residue was purified byflash chromatography (Combi-flash Rf, DCM/methanol=0-10% gradient) togive the ester intermediate which was dissolved in a mixture of THF andMeOH (4 mL, 1:1) followed by addition of NaOH (2M, 1 mL) aqueoussolution. The reaction was stirred at rt until completion ofsaponification while monitoring progress by LCMS. The reaction mixturewas acidified with HCl (1.2M), concentrated to ½ of its original volumeand diluted with ethyl acetate. The resulting solution was washed withwater, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient from 50-95% CH₃CN, 0.1% TFA) to give the title compound (65%)as a white solid. ¹H NMR (CDCl₃) δ 8.14 (m, 2H), 7.69 (d, 1H, J=8 Hz),7.42 (d, 1H, J=8 Hz), 7.14 (m, 2H), 7.31 (m, 1H), 6.64 (s, 2H),4.09-4.06 (m, 4H), 3.76 (s, 3H), 3.76 (m, 2H), 3.40-3.36 (m, 2H), 2.35(s, 6H), 2.25 (m, 2H), 2.07-2.05 (s, 6H), 1.13 and 1.08 (d, 3H, J=8 Hz).MS (ES) 659.2 (M+H).

Example 157 Preparation of(R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzoicacid I-157

The title compound (55%) was prepared according to procedures describedin Example 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 3-bromobenzoate. ¹H NMR (CDCl₃) δ 8.04 (m, 2H), 7.68 (d, 1H,J=8 Hz), 7.60 (m, 1H), 7.54 (m, 1H), 7.27 (m, 1H), 6.67 (s, 2H), 4.13(m, 1H), 4.01-3.99 (m, 2H), 3.92 and 3.90 (s, 3H), 3.60-3.55 (m, 2H),3.40-3.36 (m, 2H), 2.33 (s, 6H), 2.25 (m, 2H), 2.07-2.05 (multiple s,6H), 1.24 and 1.17 (d, 3H, J=8 Hz). MS (ES) 659.2 (M+H).

Example 158 Preparation of(R)-5-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)quinoline-8-carboxylicacid I-158

The title compound (44%) was prepared according to procedures describedin Example 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 5-bromoquinoline-8-carboxylate. ¹H NMR (MeOH-d4) δ 9.14 (m,1H), 8.82 (dd, 1H, J₁=8 Hz, J₂=16 Hz), 8.81 and 8.79 (m, 1H), 7.68 (m,2H), 7.58 (d, 1H, J=8 Hz), 7.81 and 7.68 (m, 1H), 7.32 (m, 1H), 6.31 and6.31 (s, 2H), 4.49-4.24 (m, 1H), 4.22-3.95 (m, 3H), 3.98-3.85 (multiples, 3H), 2.31 (multiple s, 6H), 2.18-2.05 (m, 8H), 1.31 and 1.13(multiple s, 3H). MS (ES) 710.2 (M+H).

Example 159 Preparation of(R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carboxylicacid I-159

The title compound (35%) was prepared according to procedures describedin Example 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 4-bromo-1-methyl-1H-indole-6-carboxylate. ¹H NMR (CDCl₃) δ7.82 (s, 1H), 7.70 (d, 1H, J=8 Hz), 7.58 (d, 1H, J=8 Hz), 7.54 (d, 1H,J=8 Hz) 7.32-7.01 (m, 3H), 6.64 (s, 2H), 4.29-4.22 (m, 3H), 4.16-4.13(m, 2H), 4.08-3.75 (multiple s, 6H), 3.73-3.38 (m, 2H), 3.37 (m, 2H),2.33 (s, 6H), 2.18-2.05 (m, 2H), 2.12-2.19 (multiple S, 6H), 1.26 and1.20 (d, 3H, J=8 Hz). MS (ES) 712.3 (M+H),

Example 160 Preparation of(R)-6-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-4-carboxylicacid I-160

The title compound (55%) was prepared according to procedures describedin Example 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 6-bromo-1-methyl-1H-indole-4-carboxylate. ¹H NMR (CDCl₃) δ8.17 (d, 1H, J=8 Hz), 7.81 (d, 1H, J=8 Hz), 7.72 (d, 1H, J=8 Hz) 7.32(m, 2H), 6.31 (s, 2H), 6.34 (tr, 1H, J=4 Hz), 4.29-4.22 (m, 3H),4.19-4.16 (m, 2H), 4.02-3.90 (multiple s, 3H), 3.84-3.78 (multiple s,3H), 3.39 (m, 3H), 2.31 (s, 6H), 2.18-2.05 (m, 2H), 2.15-2.12 (multipleS, 6H), 1.24 and 1.16 (d, 3H, J=8 Hz). MS (ES) 712.2 (M+H)

Example 161 Preparation of5-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)quinoline-8-carboxylicacid I-161

The title compound was prepared according to procedures described inExample 156 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-bromoquinoline-8-carboxylate. MS (ES) 696.2 (M+H).

Example 162 Preparation of6-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-4-carboxylicacid I-162

The title compound was prepared according to procedures described inExample 156 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-bromo-1-methyl-1H-indole-4-carboxylate. MS (ES)698.2 (M+H)

Example 163 Preparation of4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carboxylicacid I-163

The title compound was prepared according to procedures described inExample 156 using7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 4-bromo-1-methyl-1H-indole-6-carboxylate. MS (ES) 698.2 (M+H)

Example 164 Preparation of5-((3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)quinoline-8-carboxylicacid I-164

The title compound was prepared according to procedures described inExample 156 using(3R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dimethyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-bromoquinoline-8-carboxylate. MS (ES) 724.2 (M+H).

Example 165 Preparation of(S)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzoicacid I-165

The title compound was prepared according to procedures described inExample 156 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromobenzoate. MS (ES) 659.2 (M+H).

Example 166 Preparation of(S)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzoicacid I-166

The title compound was prepared according to procedures described inExample 156 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 4-bromobenzoate. MS (ES) 659.2 (M+H).

Example 167 Preparation of(S)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carboxylicacid I-167

The title compound was prepared according to procedures described inExample 156 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-oneand methyl 4-bromo-1-methyl-1H-indole-6-carboxylate. MS (ES) 712.2(M+H).

Example 168 Preparation of(S)-5-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)quinoline-8-carboxylicacid I-168

The title compound was prepared according to procedures described inExample 156 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-bromoquinoline-8-carboxylate. MS (ES) 710.2 (M+H).

Example 169 Preparation of(S)-6-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-4-carboxylicacid I-169

The title compound was prepared according to procedures described inExample 156 using(S)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-bromo-1-methyl-1H-indole-4-carboxylate. MS (ES)712.2 (M+H).

Example 170 Preparation of(R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-6-carboxylicacid I-170

The title compound was prepared according to procedures described inExample 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromo-1-methyl-1H-indole-6-carboxylate. MS (ES)712.2 (M+H).

Example 171 Preparation of(R)-3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzoicacid I-171

The title compound was prepared according to procedures described inExample 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 3-bromobenzoate. MS (ES) 659.2 (M+H).

Example 172 Preparation of(R)-4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzoicacid I-172

The title compound was prepared according to procedures described inExample 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 4-bromobenzoate. MS (ES) 659.2 (M+H).

Example 173 Preparation of(R)-5-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)quinoline-8-carboxylicacid I-173

The title compound was prepared according to procedures described inExample 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 5-bromoquinoline-8-carboxylate. MS (ES) 659.2 (M+H).

Example 174 Preparation of(R)-6-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-1-methyl-1H-indole-4-carboxylicacid I-174

The title compound was prepared according to procedures described inExample 156 using(R)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one and methyl 6-bromo-1-methyl-1H-indole-4-carboxylate. MS (ES)712.2 (M+H).

Example 175 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoicacid I-175

A solution of methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate(38 mg, 0.060 mmol), 1,3-dibromopropane (30.4 μl, 0.300 mmol), Cs₂CO₃(195 mg, 0.600 mmol) in DMF (1.200 mL) was stirred at 100° C. for 20 h.The Cs₂CO₃ was filtered and the solution was concentrated. The residuewas dissolved in mixture of EtOH (0.6 mL)/THF (0.15 mL), and 2 M LiOH(150 μl, 0.30 mmol) aqueous solution was added. The reaction mixture wasstirred at rt for 48 h then concentrated in vacuo. The residue waspurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient from 40-95% CH₃CN, 0.1% TFA) to give the title compound (16 mg)as white solid. MS (ES) 659.0 (M+H). ¹H NMR (400 MHz, DMSO-d₆): δ 7.94(s, 1H), 7.92 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.46 (d, J=7.0 Hz, 1H),7.27 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 3.98 (t, J=8.0 Hz, 2H), 3.93 (t,J=8.0 Hz, 2H), 3.78 (s, 3H), 3.60 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz,2H), 2.22 (s, 6H), 2.09-2.06 (m, 2H), 2.01 (s, 3H), 1.91 (s, 3H),1.80-1.77 (m, 2H).

Example 176 Preparation of4-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzoicacid I-176

The title compound was prepared (21 mg, 0.033 mmol) according toprocedures described in Example 175 using methyl4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate(40 mg, 0.063 mmol), 1,2-dibromoethane (27.2 μl, 0.316 mmol), Cs₂CO₃(206 mg, 0.631 mmol). MS (ES) 645.0 (M+H). ¹H NMR (400 MHz, DMSO-d₆): δ7.97 (s, 1H), 7.95 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz,1H), 7.27 (d, J=8.0 Hz, 1H), 6.75 (s, 2H), 4.06-3.98 (comp, 4H),3.85-3.82 (m, 2H), 3.87 (s, 3H), 3.26 (t, J=8.0 Hz, 2H), 2.26 (s, 6H),2.09-2.06 (m, 2H), 2.02 (s, 3H), 1.93 (s, 3H).

Example 177 Preparation of3-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoicacid I-177

The title compound was prepared (18.1 mg, 0.027 mmol) according toprocedures described in Example 175 using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate(50 mg, 0.079 mmol), 1,3-dibromopropane (40.1 μl, 0.395 mmol), Cs₂CO₃(257 mg, 0.789 mmol). MS (ES) 659.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆): δ7.93 (s, 1H), 7.85-7.82 (m, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.54-7.49(comp, 2H), 7.26 (d, J=8.0 Hz, 1H), 6.72 (s, 2H), 4.00 (t, J=6.0 Hz,2H), 3.94 (t, J=6.0 Hz, 2H), 3.77 (s, 3H), 3.59 (t, J=6.0 Hz, 2H), 3.05(t, J=6.0 Hz, 2H), 2.22 (s, 6H), 2.08-2.05 (m, 2H), 2.01 (s, 3H), 1.90(s, 3H), 1.80-1.75 (m, 2H).

Example 178 Preparation of3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzoicacid I-178

The title compound was prepared (11.3 mg, 0.018 mmol) according toprocedures described in Example 175 using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate(50 mg, 0.079 mmol), 1,2-dibromoethane (34 μL, 0.395 mmol). MS (ES)645.0 (M+H). ¹H NMR (400 MHz, DMSO-d₆): δ 7.97 (t, J=1.8 Hz, 1H), 7.81(dt, J=7.7, 1.3 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H),7.53 (d, J=7.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.74 (s, 2H), 4.05-3.97(comp, 4H), 3.87-3.80 (m, 2H), 3.77 (s, 3H), 3.25 (t, J=7.6 Hz, 2H),2.25 (s, 6H), 2.10-2.06 (m, 2H), 2.02 (s, 3H), 1.92 (s, 3H).

Example 179 Preparation of5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)furan-2-carboxylicacid I-179 Step A. Preparation of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride

To a stirred solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.200 mmol) in in DCM (4.0 mL) and DMF (1 drop) was addedoxalyl chloride (70.0 μL, 0.80 mmol) at rt. The reaction mixture wasstirred for 2 h then concentrated to give the crude title compound as ayellow solid, which was used for the next step without furtherpurification.

Step B. Example 179

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (30 mg, 0.058 mmol), methyl 5-aminofuran-2-carboxylate (12.24mg, 0.087 mmol), pyridine (23.4 μL, 0.29 mmol) in DCM (1.2 mL) wasstirred at rt for 16 h. The reaction mixture was concentrated in vacuo.The residue was dissolved in the mixture of EtOH (0.6 mL)/THF (0.15 mL),and 2 M LiOH aqueous solution (0.1 mL) was added. The reaction mixturewas stirred at rt for 20 h then acidified with HCl (aq.) (40 μl, 6N).The reaction mixture was concentrated, and the residue was purified bythe reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from40-85% CH₃CN, 0.1% TFA) to give the title compound (9.7 mg, 0.016 mmol).MS (ES) 609.0 (M+H). ¹H NMR (400 MHz, DMSO-d₆): δ 10.88 (s, 1H), 7.67(d, J=8.6 Hz, 1H), 7.25 (d, J=3.6 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 6.74(s, 2H), 6.53 (d, J=3.6 Hz, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.80 (s, 3H),3.27 (t, J=7.2 Hz, 2H), 2.26 (s, 6H), 2.07-2.03 (m, 2H), 2.03 (s, 3H),1.96 (s, 3H).

Example 180 Preparation of4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)picolinicacid I-180

The title compound was prepared (5.3 mg, 0.009 mmol) according toprocedures described in Example 179 A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (30 mg, 0.058 mmol), methyl 4-aminopicolinate (9.68 mg, 0.064mmol) and pyridine (0.023 mL, 0.289 mmol). MS (ES) 620.0 (M+H).

Example 181 Preparation of5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)nicotinicacid I-181

The title compound was prepared (15.9 mg, 0.026 mmol) according toprocedures described in Example 179 A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (30 mg, 0.058 mmol), methyl 5-aminonicotinate (9.68 mg, 0.064mmol), pyridine (9.35 μL, 0.116 mmol). MS (ES) 620.1 (M+H). ¹H NMR (400MHz, DMSO-d6): δ 10.87 (s, 1H), 10.37 (s, 1H), 9.02 (d, J=2.5 Hz, 1H),8.79 (d, J=1.9 Hz, 1H), 8.60 (t, J=2.3 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H),7.23 (d, J=8.7 Hz, 1H), 6.70 (s, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.79 (s,3H), 3.25 (t, J=7.3 Hz, 2H), 2.22 (s, 6H), 2.08-2.03 (m, 2H), 2.04 (s,3H), 1.96 (s, 3H).

Example 182 Preparation of6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)picolinicacid I-182

The title compound was prepared (7.9 mg, 0.013 mmol) according toprocedures described in Example 179 A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (30 mg, 0.058 mmol), methyl 6-aminopicolinate (9.68 mg, 0.064mmol), pyridine (9.35 μL, 0.116 mmol). MS (ES) 620.0 (M+H).

Example 183 Preparation of2-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)isonicotinicacid I-183

The title compound was prepared (34 mg, 0.055 mmol) according toprocedures described in Example 179 A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (40 mg, 0.077 mmol) and DMAP (19 mg, 0.154 mmol) in DCM (1.5mL), pyridine (6.24 μL, 0.077 mmol). MS (ES) 620.1 (M+H).

Example 184 Preparation of6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)nicotinicacid I-184

The title compound was prepared (14.5 mg, 0.023 mmol) according toprocedures described in Example 179 A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (30 mg, 0.058 mmol), methyl 6-aminonicotinate (18 mg, 0.116mmol), pyridine (4.68 μL, 0.058 mmol) and DMAP (14 mg, 0.116 mmol). MS(ES) 620.0 (M+H).

Example 185 Preparation of5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)picolinicacid I-185

The title compound was prepared (9.7 mg, 0.016 mmol) according toprocedures described in Example 179 A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (30 mg, 0.058 mmol), methyl 5-aminopicolinate (13 mg, 0.087mmol), pyridine (9.35 μL, 0.116 mmol). MS (ES) 620.1 (M+H).

Example 186 Preparation of5-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)nicotinicacid I-186

The title compound was prepared (18 mg, 0.031 mmol) according toprocedures described in Example 36 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.086 mmol), methyl 5-aminonicotinate (26 mg, 0.172 mmol),DMAP (21 mg, 0.172 mmol) and EDC (33 mg, 0.172 mmol). MS (ES) 586.0(M+H). ¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 10.38 (s, 1H), 9.06(d, J=2.5 Hz, 1H), 8.80 (d, J=1.8 Hz, 1H), 8.64 (t, J=2.2 Hz, 1H), 7.66(d, J=7.4 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.07 (dd, J=7.1, 1.0 Hz, 1H),6.73 (s, 2H), 3.99 (t, J=6.2 Hz, 2H), 3.79 (s, 3H), 3.30 (t, J=7.2 Hz,2H), 2.23 (s, 6H), 2.14 (s, 3H), 2.10-2.07 (m, 2H), 2.06 (s, 3H).

Example 187 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-187

The title compound was prepared (6.9 mg, 0.011 mmol) according toprocedures described in Example 36 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.040 mmol), methyl 3-(methylamino)benzoate (13 mg, 0.080mmol), DMAP (9.77 mg, 0.080 mmol) and EDC (11.5 mg, 0.060 mmol). MS (ES)633.0 (M+H).

Example 188 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-188

The title compound was prepared (5.5 mg, 0.001 mmol) according toprocedures described in Example 36 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (36 mg, 0.070 mmol), methyl 3-aminobenzoate (12.7 mg, 0.084 mmol),DMAP (17 mg, 0.140 mmol) and EDC (20 mg, 0.105 mmol). MS (ES) 633.0(M+H).

Example 189 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N,1-dimethyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-189

To a stirred solution of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate(46 mg, 0.073 mmol) and MeI (9.1 μL, 0.145 mmol) in THF (1.5 mL), NaH(1.7 mg, 0.073 mmol) was added. The resulting mixture was stirred overnight at rt. After 16 h, the reaction mixture was concentrated, and theresidue was purified by the reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 30-90% CH₃CN, 0.1% TFA) to give the titlecompound (18 mg, 0.028 mmol). MS (ES) 647.1 (M+H).

Example 190 Preparation of4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-190 Step A. Preparation of ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

A solution of ethyl7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate(200 mg, 0.40 mmol),4-(2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine(148 mg, 0.44 mmol), Pd(PPh₃)₄ (23 mg, 0.020 mmol) and K2CO₃ (0.60 mL,2N, 1.2 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was degassedunder Ar for 10 min. The mixture was then heated under microwave at 120°C. for 90 min in Biotage Initiator. The reaction mixture was cooled tort then concentrated in vacuo. The residue was purified by flashchromatography (0-70% EtOAc/Hex gradient) to give the title compound(150 mg, 0.24 mmol). MS(ES) 627.1 (M+H).

Step B. Preparation of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

To a solution of ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(150 mg, 0.24 mmol) in a mixture of EtOH (2.0 mL) and THF (0.5 mL) wasadded LiOH (aq. 1.0 mL, 2N, 2.0 mmol). The resulting mixture was stirredat 40° C. for 20 h then cooled to rt. The reaction mixture wasconcentrated invacuo, and the residue was purified by the reverse phaseHPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-80% CH₃CN, 0.1%TFA) to give the title compound (125 mg, 0.21 mmol) as colorless oil. MS(ES) 599.1 (M+H).

Step C. Example 190

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.033 mmol), methyl 4-aminobenzoate (5.6 mg, 0.037 mmol),DMAP (8.2 mg, 0.067 mmol) and EDC (9.6 mg, 0.05 mmol) in DCM (0.7 mL)was stirred at rt for 16 h. The solution of crude product in EtOH (0.6mL), THF (0.15 mL) and LiOH (0.1 mL) was stirred at 40° C. for 16 h. Thereaction mixture was concentrated, and the residue was purified by thereverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from30-80% CH₃CN, 0.1% TFA) to give the title compound (4.4 mg, 0.006 mmol).MS (ES) 718.0 (M+H).

Example 191 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-191

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(3,5-dimethyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.033 mmol), methyl 3-aminobenzoate (5.6 mg, 0.037 mmol),DMAP (8.2 mg, 0.067 mmol) and EDC (9.6 mg, 0.05 mmol) in DCM (0.7 mL)was stirred at rt for 16 h. EtOH (0.6 mL), THF (0.15 mL) and LiOH (0.1mL) were added to the reaction solution and the resulting mixture wasstirred at rt for 20 h. The reaction mixture was concentrated, and theresidue was purified by the reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 30-80% CH₃CN, 0.1% TFA) to give the titlecompound (9.0 mg, 0.013 mmol) as white solid. MS (ES) 718.0 (M+H).

Example 192 Preparation of1-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)indoline-6-carboxylicacid I-192

The title compound was prepared (8 mg, 0.012 mmol) according toprocedures described in Example 36 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.080 mmol), methyl indoline-6-carboxylate (21 mg, 0.120mmol), DMAP (20 mg, 0.160 mmol) and EDC (23 mg, 0.120 mmol). MS (ES)645.0 (M+H).

Example 193 Preparation of3-(3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-193

The title compound was prepared (25 mg, 0.044 mmol) according toprocedures described in Example 36 using3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (30 mg, 0.066 mmol), methyl 3-aminobenzoate (15 mg, 0.099 mmol),DMAP (16 mg, 0.132 mmol) and EDC (19 mg, 0.099 mmol). MS (ES) 573.1(M+H). ¹H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 10.23 (s, 1H), 8.32(t, J=1.8 Hz, 1H), 8.30-8.27 (m, 1H), 8.04-8.02 (m, 1H), 7.87-7.85 (m,1H), 7.69-7.65 (comp, 2H), 7.54-7.43 (comp, 4H), 7.38 (d, J=7.8 Hz, 1H),7.08 (t, J=7.4 Hz, 1H), 7.04 (dd, J=7.1, 1.2 Hz, 1H), 6.92 (d, J=7.2 Hz,1H), 4.23 (t, J=6.0 Hz, 2H), 3.79 (s, 3H), 3.44 (t, J=7.5 Hz, 2H),2.30-2.23 (m, 2H), 2.13 (s, 3H), 2.05 (s, 3H).

Example 194 Preparation of5-(3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)nicotinicacid I-194

The title compound was prepared (17 mg, 0.030 mmol) according toprocedures described in Example 36 using3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (30 mg, 0.066 mmol), methyl 5-aminonicotinate (15 mg, 0.099 mmol),DMAP (16 mg, 0.132 mmol) and EDC (19 mg, 0.099 mmol). MS (ES) 574.0(M+H). ¹H NMR (400 MHz, DMSO-d6): δ 10.79 (s, 1H), 10.42 (s, 1H), 9.09(d, J=2.5 Hz, 1H), 8.81 (d, J=1.8 Hz, 1H), 8.68 (t, J=2.2 Hz, 1H), 8.29(dd, J=7.6, 2.1 Hz, 1H), 7.86 (dd, J=6.5, 2.0 Hz, 1H), 7.69 (d, J=7.3Hz, 1H), 7.54-7.46 (comp, 2H), 7.44 (d, J=8.2 Hz, 1H), 7.38 (t, J=8.0Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.06 (dd, J=7.1, 1.2 Hz, 1H), 6.92 (d,J=7.0 Hz, 1H), 4.23 (t, J=6.0 Hz, 2H), 3.79 (s, 3H), 3.45 (t, J=7.4 Hz,2H), 2.30-2.25 (m, 2H), 2.14 (s, 3H), 2.06 (s, 3H).

Example 195 Preparation of3-(N-methyl-3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-195

The title compound was prepared (19 mg, 0.032 mmol) according toprocedures described in Example 36 using3-(3-(naphthalen-1-yloxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (30 mg, 0.066 mmol), methyl 3-(methylamino)benzoate (16 mg, 0.099mmol), DMAP (16 mg, 0.13 mmol) and EDC (19 mg, 0.099 mmol). MS (ES)587.1 (M+H).

Example 196 Preparation of3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-196

The title compound was prepared (29 mg, 0.050 mmol) according toprocedures described in Example 36 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.086 mmol), methyl 3-aminobenzoate (26 mg, 0.172 mmol),DMAP (21 mg, 0.172 mmol) and EDC (33 mg, 0.172 mmol). MS (ES) 585.1(M+H). ¹H NMR (400 MHz, DMSO-d6): δ 10.79 (s, 1H), 10.20 (s, 1H), 8.28(t, J=1.8 Hz, 1H), 7.99 (ddd, J=8.2, 2.2, 0.9 Hz, 1H), 7.67 (dt, J=7.8,1.3 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.12 (t,J=7.5 Hz, 1H), 7.04 (dd, J=7.1, 1.1 Hz, 1H), 6.74 (s, 2H), 4.00 (t,J=6.3 Hz, 2H), 3.78 (s, 3H), 3.29 (t, J=7.3 Hz, 2H), 2.24 (s, 6H), 2.13(s, 3H), 2.10-2.07 (m, 2H), 2.05 (s, 3H).

Example 197 Preparation of3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-197

The title compound was prepared (13 mg, 0.022 mmol) according toprocedures described in Example 1 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.086 mmol), methyl 3-(methylamino)benzoate (28 mg, 0.172mmol), DMAP (21 mg, 0.172 mmol) and EDC (33 mg, 0.172 mmol). MS (ES)599.1 (M+H).

Example 198 Preparation of5-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)nicotinicacid I-198

The title compound was prepared (20 mg, 0.031 mmol) according toprocedures described in Example 175 using methyl5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)nicotinate(38 mg, 0.060 mmol), 1,2-dibromoethane (26 μL, 0.299 mmol), Cs₂CO₃ (195mg, 0.60 mmol). MS (ES) 646.0 (M+H). ¹H NMR (400 MHz, DMSO-d6): δ 8.93(s, 1H), 8.86 (s, 1H), 8.31 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.28 (d,J=8.0 Hz, 1H), 6.75 (s, 2H), 4.09-4.06 (m, 2H), 4.00 (t, J=6.0 Hz, 2H),3.89-3.85 (m, 2H), 3.77 (s, 3H), 3.26 (t, J=8.0 Hz, 2H), 2.26 (s, 6H),2.08-2.05 (m, 2H), 2.03 (s, 3H), 1.93 (s, 3H).

Example 199 Preparation of5-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)nicotinicacid I-199

The title compound was prepared (5.7 mg, 0.009 mmol) according toprocedures described in Example 175 using methyl5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)nicotinate(32 mg, 0.050 mmol), 1,3-dibromopropane (26 μL, 0.25 mmol), Cs₂CO₃ (164mg, 0.50 mmol). MS (ES) 660.0 (M+H).

Example 200 Preparation of2-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)isonicotinicacid I-200

The title compound was prepared (6 mg, 0.009 mmol) according toprocedures described in Example 175 using methyl2-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)isonicotinate(60 mg, 0.095 mmol), 1,3-dibromopropane (48 μL, 0.47 mmol), Cs₂CO₃ (308mg, 0.95 mmol). MS (ES) 660.0 (M+H).

Example 201 Preparation of6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)nicotinicacid I-201

The title compound was prepared (5.6 mg) according to proceduresdescribed in Example 175 using methyl6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)nicotinate(40 mg, 0.063 mmol), 1,3-dibromopropane (32 μL, 0.315 mmol), Cs₂CO₃ (205mg, 0.63 mmol). MS (ES) 660.0 (M+H).

Example 202 Preparation of1-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)indoline-4-carboxylicacid I-202

The title compound was prepared (36 mg, 0.059 mmol) according toprocedures described in Example 36 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.086 mmol), methyl indoline-4-carboxylate (30 mg, 0.17mmol), DMAP (21 mg, 0.17 mmol) and EDC (33 mg, 0.17 mmol). MS (ES) 611.1(M+H).

Example 203 Preparation of1-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperidine-4-carboxylicacid I-203

The title compound was prepared (38 mg, 0.066 mmol) according toprocedures described in Example 36 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.086 mmol), methyl piperidine-4-carboxylate (25 mg, 0.172mmol), DMAP (21 mg, 0.172 mmol) and EDC (33 mg, 0.172 mmol). MS (ES)577.1 (M+H).

Example 204 Preparation of2-(1-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperidin-4-yl)aceticacid I-204

The title compound was prepared (26 mg, 0.044 mmol) according toprocedures described in Example 36 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.086 mmol), ethyl 2-(piperidin-4-yl)acetate (29 mg, 0.172mmol), DMAP (21 mg, 0.172 mmol) and EDC (33 mg, 0.172 mmol). MS (ES)591.1 (M+H).

Example 205 Preparation of2-(4-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)phenyl)aceticacid I-205

The title compound was prepared (37 mg, 0.063 mmol) according toprocedures described in Example 36 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.086 mmol), methyl 2-(4-aminophenyl)acetate (28 mg, 0.17mmol), DMAP (21 mg, 0.17 mmol) and EDC (33 mg, 0.17 mmol). MS (ES) 599.1(M+H).

Example 206 Preparation of2-(3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)phenyl)aceticacid I-206

The title compound was prepared (45 mg, 0.075 mmol) according toprocedures described in Example 36 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.086 mmol), methyl 2-(3-aminophenyl)acetate (28 mg, 0.17mmol), DMAP (21 mg, 0.172 mmol) and EDC (33 mg, 0.17 mmol). MS (ES)599.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆): δ 10.82 (s, 1H), 10.04 (s, 1H),7.65-7.62 (comp, 2H), 7.58 (s, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.12 (t,J=7.5 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.76 (s,2H), 4.00 (t, J=6.1 Hz, 2H), 3.79 (s, 3H), 3.58 (s, 2H), 3.29 (t, J=7.4Hz, 2H), 2.26 (s, 6H), 2.13 (s, 3H), 2.10-2.07 (m, 2H), 2.06 (s, 3H).

Example 207 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-(4-methylpiperazin-1-yl)benzoicacid I-207

The title compound was prepared (9.1 mg, 0.013 mmol) according toprocedures described in Example 36 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (99 mg, 0.20 mmol), methyl3-amino-5-(4-methylpiperazin-1-yl)benzoate (54 mg, 0.22 mmol), DMAP (48mg, 0.39 mmol) and EDC (75 mg, 0.39 mmol). MS (ES) 717.1 (M+H).

Example 208 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-morpholinobenzoicacid I-208

The title compound was prepared (23 mg, 0.032 mmol) according toprocedures described in Example 36 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (68 mg, 0.136 mmol), methyl 3-amino-5-morpholinobenzoate (35.3 mg,0.149 mmol), DMAP (33.2 mg, 0.272 mmol) and EDC (52.1 mg, 0.272 mmol).MS (ES) 704.1 (M+H).

Example 209 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-((tetrahydro-2H-pyran-4-yl)amino)benzoicacid I-209

The title compound was prepared (13 mg, 0.019 mmol) according toprocedures described in Example 36 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (73 mg, 0.15 mmol), methyl3-amino-5-((tetrahydro-2H-pyran-4-yl)amino)benzoate (40 mg, 0.16 mmol),DMAP (36 mg, 0.29 mmol) and EDC (56 mg, 0.29 mmol). MS (ES) 718.0 (M+H).

Example 210 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-((2-(dimethylamino)ethyl)(methyl)amino)benzoicacid I-210

The title compound was prepared (19 mg, 0.026 mmol) according toprocedures described in Example 36 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (116 mg, 0.23 mmol), methyl3-amino-5-((2-(dimethylamino)ethyl)(methyl)amino)benzoate (70 mg, 0.28mmol), DMAP (57 mg, 0.46 mmol) and EDC (89 mg, 0.46 mmol). MS (ES) 719.1(M+H).

Example 211 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-((2-(dimethylamino)ethyl)(methyl)amino)benzoicacid I-211

The title compound was prepared (6.3 mg, 0.008 mmol) according toprocedures described in Example 175 using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-((2-(dimethylamino)ethyl)(methyl)amino)benzoate(60 mg, 0.082 mmol), 1,3-dibromopropane (42 μL, 0.41 mmol), Cs₂CO₃ (266mg, 0.82 mmol). MS (ES) 759.1 (M+H).

Example 212 Preparation of4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-212

The title compound was prepared (12 mg, 0.019 mmol) according toprocedures described in Example 179 A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (40 mg, 0.077 mmol), methyl 4-(methylamino)benzoate (26 mg,0.15 mmol), DMAP (19 mg, 0.15 mmol) and pyridine (6.2 μL, 0.077 mmol).MS (ES) 619.9 (M+H).

Example 213 Preparation of3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-morpholinobenzoicacid I-213

The title compound was prepared (10 mg, 0.014 mmol) according toprocedures described in Example 179 A and B using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-morpholinobenzoate(42 mg, 0.058 mmol), 1,2-dibromoethane (25 μL, 0.29 mmol) and Cs₂CO₃(190 mg, 0.58 mmol). MS (ES) 730.0 (M+H).

Example 214 Preparation of3-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-5-((tetrahydro-2H-pyran-4-yl)amino)benzoicacid I-214

The title compound was prepared (11 mg, 0.015 mmol) according toprocedures described in Example 179 A and B using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-((tetrahydro-2H-pyran-4-yl)amino)benzoate(43 mg, 0.059 mmol), 1,2-dibromoethane (25 μL, 0.29 mmol) and Cs₂CO₃(191 mg, 0.59 mmol). MS (ES) 744.1 (M+H).

Example 215 Preparation of3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-(dimethylamino)benzoicacid I-215

The title compound was prepared (7 mg, 0.011 mmol) according toprocedures described in Example 36 using of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.20 mmol), methyl 3-amino-5-(dimethylamino)benzoate (43mg, 0.22 mmol), DMAP (49 mg, 0.40 mmol) and EDC (77 mg, 0.40 mmol). MS(ES) 662.1 (M+H).

Example 216 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(dimethylamino)benzoicacid I-216

The title compound was prepared (16 mg, 0.023 mmol) according toprocedures described in Example 179 A and B using methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-(dimethylamino)benzoate(42 mg, 0.062 mmol), 1,3-dibromopropane (32 μL, 0.31 mmol) and Cs₂CO₃(202 mg, 0.62 mmol). MS (ES) 702.0 (M+H).

Example 217 Preparation of3-bromo-5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoicacid I-217 Step A. Preparation of methyl3-bromo-5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (200 mg, 0.40 mmol), methyl 3-amino-5-bromobenzoate (101 mg, 0.44mmol), DMAP (98 mg, 0.80 mmol) and EDC (153 mg, 0.80 mmol) in DCM (8.0mL) was stirred at rt for 16 h. The reaction mixture was concentrated invacuo, and the residue was purified by silica gel flash chromatography(ISCO, 0-70% EtOAc/Hex gradient) to give title compound (255 mg, 0.36mmol). MS(ES) 712.9 (M+H).

Step B. Example 217

To a solution of methyl3-bromo-5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)(25 mg, 0.035 mol) in a mixture of EtOH (0.6 mL), THF (0.15 mL) wasadded LiOH (aq. 0.1 mL, 2N, 0.20 mmol) at rt. The reaction mixture wasstirred for 20 h at rt then concentrated in vacuo. The residue waspurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient from 30-90% CH₃CN, 0.1% TFA) to give the title compound (16.7mg, 0.024 mmol) as white solid. MS (ES) 698.8 (M+H).

Example 218 Preparation of3-bromo-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoicacid I-218 Step A. Preparation of methyl3-bromo-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoate

A solution of methyl3-bromo-5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate(230 mg, 0.323 mmol), 1,3-dibromopropane (164 μL, 1.6 mmol), Cs₂CO₃(1.05 g, 3.2 mmol) in DMF (6.5 mL) was stirred at 100° C. for 16 h. TheCs₂CO₃ was filtered, and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel flash chromatography (ISCO 0-70%EtOAc/Hex gradient) to give the title compound (110 mg, 0.15 mmol). MS(ES) 752.9 (M+H).

Step B. Example 218

To a solution of methyl3-bromo-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoate(20 mg, 0.027 mmol) in THF (266 μL) was added LiOH (aq. 2N, 66.4 μL,0.133 mmol) at rt. The reaction mixture was stirred for 20 h at rt thenconcentrated. The residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 40-95% CH₃CN, 0.1% TFA)to give title compound (10 mg, 0.014 mmol). MS (ES) 738.9 (M+H).

Example 219 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(4-methylpiperazin-1-yl)benzoicacid I-219 Step A. Preparation of methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(4-methylpiperazin-1-yl)benzoate

A solution of methyl3-bromo-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoate(37 mg, 0.049 mmol), 1-methylpiperazine (7.39 mg, 0.074 mmol), BINAP(3.06 mg, 4.92 μmol) and Cs₂CO₃ (48.1 mg, 0.148 mmol) in Toluene (500μL) was degassed under Argon for 10 min. palladium(II) acetate (1.1 mg,4.9 μmol) was added and the resulting mixture was then heated to 100° C.for 16 h. The reaction mixture was filtered, and the filtrate waspurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient from 30-80% CH₃CN, 0.1% NH₄OH) to give the title compound (5mg) as a brown solid. MS (ES) 771.1 (M+H).

Step B. Example 219

To a solution of methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(4-methylpiperazin-1-yl)benzoate(5 mg, 0.006 mmol) in a mixture of EtOH (100 μL) and THF (50 μL) wasadded LiOH (aq. 30 μL, 2N). The reaction mixture was stirred at 40° C.for 15 h, acidified by addition of TFA and concentrated. The residue waspurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient from 30-80% CH₃CN, 0.1% NH₄OH) to give the title compound (3mg). MS (ES) 757.0 (M+H).

Example 220 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-methylbenzoicacid I-220 Step A. Preparation of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-methylbenzoate

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.200 mmol), methyl 3-amino-5-methylbenzoate (36 mg, 0.220mmol), DMAP (49 mg, 0.400 mmol) and EDC (77 mg, 0.400 mmol) in DCM (4mL) was stirred at rt for 16 h. The reaction mixture was concentrated invacuo, and the residue was purified by silica gel flash chromatography(ISCO, 0-60% EtOAc/Hex gradient) to give the title compound (48 mg,0.074 mmol). MS(ES) 647.1 (M+H).

Step B. Preparation of methyl3-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-methylbenzoate

A solution of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-methylbenzoate(48 mg, 0.074 mmol), 1,3-dibromopropane (38 μL, 0.371 mmol), Cs₂CO₃ (241mg, 0.74 mmol) in DME (15 mL) was stirred at 100° C. for 16 h. Thereaction mixture was cooled to rt, filtered, and the filtrate wasconcentrated. The residue was purified by silica gel flashchromatography (ISCO, 0-70% EtOAc/Hex gradient) to give the titlecompound (24 mg, 0.035 mmol). MS (ES) 687.0 (M+H).

Step C. Example 220

To a solution of methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-methylbenzoate(24 mg, 0.035 mmol) in THF (350 μl) was added LiOH (aq. 2N, 87 μL, 0.175mmol). The reaction mixture was stirred at rt for 20 h thenconcentrated. The residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 40-90% CH₃CN, 0.1% TFA)to give the title compound (8.2 mg, 0.012 mmol). MS(ES) 673.0 (M+H).

Example 221 Preparation of3-chloro-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoicacid I-221 Step A. Preparation of methyl3-chloro-5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate

The title compound was prepared (73 mg, 0.109 mmol) according toprocedures described in Example 220 Step A using of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (80 mg, 0.160 mmol), methyl 3-amino-5-chlorobenzoate (32.6 mg,0.176 mmol), DMAP (39.1 mg, 0.320 mmol) and EDC (61.3 mg, 0.320 mmol).MS (ES) 667.0 (M+H).

Step B. Example 221

A solution of methyl3-chloro-5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate(73 mg, 0.109 mmol), 1,3-dibromopropane (0.033 ml, 0.328 mmol), Cs₂CO₃(178 mg, 0.546 mmol) in DMF (1 mL) was stirred at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was dissolved in THF (0.5 mL) and LiOH (aq. 0.3 mL, 2N). Thereaction mixture was stirred at 40° C. for 15 h then concentrated. Theresidue was purified by the reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 40-90% CH₃CN, 0.1% TFA) to give title compound(17 mg, 0.024 mmol). MS (ES) 693.0 (M+H), ¹H NMR (400 MHz, DMSO-d₆): δ7.88 (m, 1H), 7.79 (m, 1H), 7.73-7.71 (comp, 2H), 7.27 (d, J=8.0 Hz,1H), 6.73 (s, 2H), 4.01 (t, J=8.0 Hz, 2H), 3.94 (t, J=6.0 Hz, 2H), 3.78(s, 3H), 3.63 (t, J=6.0 Hz, 2H), 3.06 (t, J=8.0 Hz, 2H), 2.23 (s, 6H),2.09-2.06 (m, 2H), 2.01 (s, 3H), 1.91 (s, 3H), 1.77 (t, 2H).

Example 222 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(trifluoromethyl)benzoicacid I-222 Step A. Preparation of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-(trifluoromethyl)benzoate

The title compound was prepared (72 mg, 0.10 mmol) according toprocedures described in Example 220 Step A using of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (80 mg, 0.16 mmol), methyl 3-amino-5-(trifluoromethyl)benzoate (38mg, 0.18 mmol), DMAP (39 mg, 0.32 mmol) and EDC (61 mg, 0.32 mmol). MS(ES) 700.9 (M+H).

Step B. Example 222

A solution of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-(trifluoromethyl)benzoate(72 mg, 0.10 mmol), 1,3-dibromopropane (0.031 mL, 0.31 mmol), Cs₂CO₃(167 mg, 0.51 mmol) in DMF (1 mL) was stirred at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was dissolved in THF (0.5 mL), and LiOH (aq. 2N, 0.3 mL, 0.6mmol). The reaction mixture was stirred at 40° C. for 15 h thenconcentrated. The residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 40-90% CH₃CN, 0.1% TFA)to give the title compound (15 mg, 0.021 mmol). MS (ES) 727.0 (M+H), ¹HNMR (400 MHz, DMSO-d₆): δ 8.16 (s, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.72(d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 4.04 (t, J=8.0Hz, 2H), 3.96 (t, J=6.0 Hz, 2H), 3.78 (s, 3H), 3.67 (t, J=6.0 Hz, 2H),3.06 (t, J=8.0 Hz, 2H), 2.22 (s, 6H), 2.09-2.06 (m, 2H), 2.02 (s, 3H),1.91 (s, 3H), 1.80-1.76 (m, 2H).

Example 223 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-fluorobenzoicacid I-223 Step A. Preparation of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-fluorobenzoate

The title compound was prepared (75 mg, 0.115 mmol) according toprocedures described in Example 220 Step A using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (80 mg, 0.16 mmol), methyl 3-amino-5-fluorobenzoate (41 mg, 0.24mmol), DMAP (39 mg, 0.32 mmol) and EDC (61 mg, 0.32 mmol). MS (ES) 651.0(M+H).

Step B. Example 223

A solution of methyl3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-5-fluorobenzoate(75 mg, 0.11 mmol), 1,3-dibromopropane (0.035 mL, 0.34 mmol), Cs₂CO₃(188 mg, 0.58 mmol) in DMF (2 mL) was stirred at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was dissolved in THF (0.5 mL) and LiOH (aq. 2N 0.3 mL, 0.6 mmol)was added. The reaction mixture was stirred at 40° C. for 15 h thenconcentrated. The residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-85% CH₃CN, 0.1% TFA)to give the title compound (28 mg, 0.041 mmol). MS (ES) 677.0 (M+H).

Example 224 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(hydroxymethyl)benzoicacid I-224 Step A. Preparation of methyl3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate

The title compound was prepared (75 mg, 0.12 mmol) according toprocedures described in Example 220 Step A using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (230 mg, 0.46 mmol), methyl3-amino-5-(((tert-butyldimethylsilyl)oxy)methyl)benzoate (149 mg, 0.51mmol), DMAP (112 mg, 0.92 mmol) and EDC (176 mg, 0.92 mmol). MS (ES)777.1 (M+H).

Step B. Preparation of methyl3-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(hydroxymethyl)benzoate

A solution of methyl3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)benzoate(240 mg, 0.31 mmol), 1,3-dibromopropane (0.157 mL, 1.54 mmol), Cs₂CO₃(503 mg, 1.54 mmol) in DMF (4 mL) was stirred at 60° C. for 2 h. Thereaction mixture was filtered, and the filtrate was concentrated. Theresidue was dissolved in THF (5 mL), and TBAF (1 mL, 1.0 mmol, 1M inTHF) was added. The reaction mixture was stirred at rt for 1 h thenconcentrated. The residue was purified by silica gel flashchromatography (ISCO 0-15% MeOH/DCM gradient) to give the title compound(214 mg, 0.30 mmol). MS (ES) 703.0 (M+H).

Step C. Example 224

To a solution of methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(hydroxymethyl)benzoate(40 mg, 0.057 mmol) in THF (0.6 mL) was added LiOH (aq. 2N, 140 μL, 0.28mmol). The reaction mixture was stirred at rt for 20 h thenconcentrated. The residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-80% CH₃CN, 0.1% TFA)to give the title compound (28 mg, 0.041 mmol). MS (ES) 689.1 (M+H), ¹HNMR (400 MHz, DMSO-d₆): δ 7.84 (s, 1H), 7.81 (s, 1H), 7.71 (d, J=8.0 Hz,1H), 7.51 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 6.74 (s, 2H), 2.51 (s, 2H),4.02-3.94 (comp, J=4H), 3.78 (s, 3H), 3.60 (t, J=6.0 Hz, 2H), 3.05 (t,J=8.0 Hz, 2H), 2.28 (s, 6H), 2.08-2.06 (m, 2H), 2.01 (s, 3H), 1.91 (s,3H), 1.80-1.76 (m, 2H).

Example 225 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(pyrrolidin-1-ylmethyl)benzoicacid I-225

A solution of methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(hydroxymethyl)benzoate(30 mg, 0.043 mmol), DIPEA (15 μL, 0.085 mmol) and MsCl (6.6 μl, 0.085mmol) in DCM (400 μL) was stirred at 0° C. for 1 h then pyrrolidine (35μL, 0.43 mmol) was added. The resulting mixture was warmed to rt,stirred additional 1 h then concentrated. The residue was dissolved inTHF (0.2 mL) and LiOH (aq. 2N, 0.1 mL, 0.2 mmol) was added. The mixturewas stirred at 40° C. for 15 h then concentrated. The residue waspurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient from 30-80% CH₃CN, 0.1% NH₄OH) to give the title compound (8.5mg, 0.011 mmol). MS (ES) 742.0 (M+H).

Example 226 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-((dimethylamino)methyl)benzoicacid I-226

The title compound was prepared (9 mg, 0.013 mmol) according toprocedures described in Example 225 using methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(hydroxymethyl)benzoate(20 mg, 0.028 mmol), DIPEA (15 μL, 0.085 mmol) and MsCl (4.4 μL, 0.057mmol) and dimethylamine (1M, 85 μL, 0.085 mmol). MS (ES) 716.1 (M+H), ¹HNMR (400 MHz, DMSO-d₆): δ 8.10 (s, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.73(d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 4.36 (d, J=4.0Hz, 2H), 4.02-3.94 (comp, 4H), 3.78 (s, 3H), 3.65 (t, J=6.0 Hz, 2H),3.07 (t, J=6.0 Hz, 2H), 2.77 (s, 3H), 2.76 (s, 3H), 2.22 (s, 6H),2.08-2.06 (m, 2H), 2.02 (s, 3H), 1.92 (s, 3H), 1.85-1.80 (m, 2H).

Example 227 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(morpholinomethyl)benzoicacid I-227

The title compound was prepared (20 mg, 0.026 mmol) according toprocedures described in Example 225 using of methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(hydroxymethyl)benzoate(30 mg, 0.043 mmol), DIPEA (15 μL, 0.085 mmol) and MsCl (6.6 μL, 0.085mmol) and morpholine (19 μL, 0.21 mmol). MS (ES) 758.1 (M+H), ¹H NMR(400 MHz, DMSO-d₆): δ 8.10 (s, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.73 (d,J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 4.44 (s, 2H),4.02-3.95 (comp, 6H), 3.78 (s, 3H), 3.70-3.64 (comp, 4H), 3.33-3.29 (m,2H), 3.17-3.14 (m, 2H), 3.06 (t, J=8.0 Hz, 2H), 2.23 (s, 6H), 2.10-2.07(m, 2H), 2.02 (s, 3H), 1.92 (s, 3H), 1.85-1.80 (m, 2H).

Example 228 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-((4-methylpiperazin-1-yl)methyl)benzoicacid I-228

The title compound was prepared (17 mg, 0.021 mmol) according toprocedures described in Example 225 using of methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(hydroxymethyl)benzoate(30 mg, 0.043 mmol), DIPEA (15 μL, 0.085 mmol) and MsCl (6.6 μL, 0.085mmol) and 1-methylpiperazine (24 μL, 0.21 mmol). MS (ES) 771.1 (M+H), ¹HNMR (400 MHz, DMSO-d₆): δ 7.91 (s, 1H), 7.87 (s, 1H), 7.72 (d, J=8.0 Hz,1H), 7.56 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 4.01 (t, J=8.0Hz, 2H), 3.96 (t, J=6.0 Hz, 2H), 3.79-3.75 (m, 2H), 3.78 (s, 3H), 3.62(t, J=6.0 Hz, 2H), 3.42 (s, 2H), 3.09-3.05 (comp, 6H), 2.80 (s, 3H),2.23 (s, 6H), 2.09-2.05 (m, 4H), 2.02 (s, 3H), 1.91 (s, 3H), 1.82-1.77(m, 2H).

Example 229 Preparation of3-((1H-imidazol-1-yl)methyl)-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoicacid I-229

The title compound was prepared (13 mg, 0.021 mmol) according toprocedures described in Example 225 using of methyl3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(hydroxymethyl)benzoate(30 mg, 0.043 mmol), DIPEA (15 μL, 0.085 mmol) and MsCl (6.6 μl, 0.085mmol) and imidazole (14 mg, 0.21 mmol). MS (ES) 739.0 (M+H).

Example 230 Preparation of2-chloro-6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)isonicotinicacid I-230 Step A. Preparation of methyl2-chloro-6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)isonicotinate

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonylchloride (100 mg, 0.19 mmol), DMAP (47 mg, 0.39 mmol), Pyridine (31 μL,0.39 mmol) in DCM (3.8 mL) was stirred at rt for 10 min, and methyl2-amino-6-chloroisonicotinate (40 mg, 0.21 mmol) was added. Theresulting mixture was stirred at rt for 15 h then concentrated. Theresidue was purified by silica gel flash chromatography (ISCO, 0-60%EtOAc/Hex gradient) to give the title compound (100 mg, 0.149 mmol). MS(ES) 667.9 (M+H).

Step B. Example 230

A solution of methyl2-chloro-6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)isonicotinate(100 mg, 0.149 mmol), 1,3-dibromopropane (46 μL, 0.448 mmol), Cs₂CO₃(244 mg, 0.747 mmol) in DMF (2.1 mL) was stirred at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was dissolved in THF (0.3 mL), and LiOH (aq. 2N, 0.1 mL, 0.2mmol). The reaction mixture was stirred at 40° C. for 15 h thenconcentrated. The residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-90% CH₃CN, 0.1% TFA)to give the title compound (5 mg, 0.007 mmol). MS (ES) 696.0 (M+H).

Example 231 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(pyridin-4-yl)benzoicacid I-231

A solution of methyl3-bromo-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoate(30 mg, 0.040 mmol), pyridin-4-ylboronic acid (6.0 mg, 0.048 mmol),Pd(PPh₃)₄ (2.3 mg, 2.0 μmol) and CsF (18.17 mg, 0.120 mmol) in ethanol(100 μL) and DME (200 μL) was degassed under Ar for 10 min. The mixturewas then heated under microxave at 120° C. (Biotage Initiator) for 25min. The reaction mixture was cooled to rt then LiOH (aq. 2N, 0.3 mL)was added. The resulting mixture was heated under microwave at 100° C.(Biotage Initiator) for additional 20 min. The reaction mixture wasconcentrated, and the residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-75% CH₃CN, 0.1% TFA)to give the title compound (12 mg, 0.016 mmol). MS (ES) 736.0 (M+H).

Example 232 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(2-methylpyridin-3-yl)benzoicacid I-232

The title compound was prepared (30 mg, 0.021 mmol) according toprocedures described in Example 231 using3-bromo-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoate(40 mg, 0.053 mmol), (2-methylpyridin-3-yl)boronic acid (8.74 mg, 0.064mmol), Pd(PPh₃)₄ (3.07 mg, 2.66 μmol) and CsF (24.22 mg, 0.159 mmol). MS(ES) 750.0 (M+H), ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.31-8.28(m, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.83-7.79 (m, 1H), 7.76 (s, 1H),7.73 (d, J=8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 6.72 (s, 2H), 4.02 (t,J=6.0 Hz, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.77 (s, 3H), 3.68 (t, J=6.0 Hz,2H), 3.07 (t, J=8.0 Hz, 2H), 2.61 (s, 3H), 2.21 (s, 6H), 2.12-2.06 (m,2H), 2.01 (s, 3H), 1.91 (s, 3H), 1.83-1.78 (m, 2H).

Example 233 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(3-methylpyridin-4-yl)benzoicacid I-233

The title compound was prepared (12 mg, 0.016 mmol) according toprocedures described in Example 231 using3-bromo-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoate(40 mg, 0.053 mmol), (3-methylpyridin-4-yl)boronic acid (9.0 mg, 0.064mmol), Pd(PPh₃)₄ (3.1 mg, 2.7 μmol) and CsF (24 mg, 0.16 mmol). MS (ES)750.0 (M+H), ¹H NMR (400 MHz, DMSO-d₆): δ 8.79 (s, 1H), 8.72 (d, J=4.0Hz, 1H), 8.09 (s, 1H), 7.89 (s, 1H), 7.74-7.72 (comp, 3H), 7.27 (d, J=8Hz, 1H), 6.72 (s, 2H), 4.06-4.04 (m, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.78(s, 3H), 3.69 (t, J=6.0 Hz, 2H), 3.07 (t, J=8.0 Hz, 2H), 2.38 (s, 3H),2.20 (s, 6H), 2.09-2.05 (m, 2H), 2.01 (s, 3H), 1.91 (s, 3H), 1.83-1.78(m, 2H).

Example 234 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(4-methylpyridin-3-yl)benzoicacid I-234

The title compound was prepared (14 mg, 0.019 mmol) according toprocedures described in Example 231 using3-bromo-5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoate(40 mg, 0.053 mmol), (4-methylpyridin-3-yl)boronic acid (8.7 mg, 0.064mmol), Pd(PPh₃)₄ (3.1 mg, 2.7 μmol) and CsF (24 mg, 0.16 mmol). MS (ES)750.0 (M+H).

Example 235 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-5-(1-methyl-1H-pyrrol-2-yl)benzoicacid I-235

The title compound was prepared (11 mg, 0.015 mmol) according toprocedures described in Example 231 using3-bromo-5-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoate(40 mg, 0.053 mmol),1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (13mg, 0.064 mmol), Pd(PPh₃)₄ (3.1 mg, 2.7 μmol) and CsF (24 mg, 0.16mmol). MS (ES) 738.0 (M+H).

Example 236 Preparation of2-(3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)phenyl)aceticacid I-236 Step A. Preparation of methyl2-(3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)phenyl)acetate

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.100 mmol), methyl 2-(3-aminophenyl)acetate (33 mg, 0.20mmol), DMAP (24 mg, 0.20 mmol) and EDC (38 mg, 0.20 mmol) in DCM (2 mL)was stirred at rt for 16 h. The reaction mixture was concentrated, andthe residue was purified by silica gel flash chromatography (ISCO 0-10%MeOH/DCM gradient) to give the title compound (40 mg, 0.062 mmol). MS(ES) 647.0 (M+H).

Step B. Example 236

A solution of methyl2-(3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)phenyl)acetate(40 mg, 0.062 mmol), 1,3-dibromopropane (0.019 ml, 0.19 mmol), Cs₂CO₃(101 mg, 0.31 mmol) in DMF (2 ml) was stirred at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was dissolved in THF (0.5 mL) and LiOH (aq. 2N, 0.3 ml, 0.6mmol) was added. The reaction mixture was stirred at 40° C. for 15 hthen concentrated. The residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-80% CH₃CN, 0.1% TFA)to give the title compound (15 mg, 0.022 mmol). MS (ES) 673.0 (M+H).

Example 237 Preparation of2-(4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)phenyl)aceticacid I-237

The title compound was prepared (10 mg, 0.015 mmol) according toprocedures described in Example 236 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.10 mmol), methyl 2-(4-aminophenyl)acetate (33 mg, 0.20mmol), DMAP (24 mg, 0.20 mmol) and EDC (38 mg, 0.20 mmol). MS (ES) 673.0(M+H).

Example 238 Preparation of6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1H-indole-4-carboxylicacid I-238 Step A. Preparation of methyl6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1H-indole-4-carboxylate

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.10 mmol), methyl 6-amino-1H-indole-4-carboxylate (23 mg,0.12 mmol), DMAP (24 mg, 0.20 mmol) and EDC (38 mg, 0.20 mmol) in DCM (2mL) was stirred at rt for 16 h. The reaction mixture was concentrated,and the residue was purified by silica gel flash chromatography (ISCO0-70% EtOAc/Hex gradient) to give the title compound (35 mg, 0.052mmol). MS (ES) 672.0 (M+H).

Step B. Example 238

A mixture of methyl6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1H-indole-4-carboxylate(35 mg, 0.052 mmol), LiOH (aq. 2N, 130 μL, 0.26 mmol) in THF (500 μL)was stirred at rt for 15. The reaction mixture was concentrated, and theresidue was purified by the reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 30-80% CH₃CN, 0.1% TFA) to give the titlecompound (13 mg, 0.020 mmol). MS (ES) 658.0 (M+H).

Example 239 Preparation of6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-4-carboxylicacid I-239 Step A. Preparation of methyl6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1-methyl-1H-indole-4-carboxylate

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.20 mmol), methyl6-amino-1-methyl-1H-indole-4-carboxylate (49 mg, 0.240 mmol), DMAP (49mg, 0.40 mmol) and EDC (77 mg, 0.40 mmol) in DCM (4 mL) was stirred atrt for 16 h. The reaction mixture was concentrated, and the residue waspurified by silca gel flash chromatography (ISCO 0-10% MeOH/DCMgradient) to give title compound (80 mg, 0.117 mmol). MS (ES) 686.0(M+H).

Step B. Example 239

A mixture of methyl6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1-methyl-1H-indole-4-carboxylate(80 mg, 0.117 mmol), 1,3-dibromopropane (36 μL, 0.35 mmol), Cs₂CO₃ (190mg, 0.58 mmol) in DMF (1.5 mL) was stirred at 60° C. for 2 h. Thereaction mixture was filtered, and the filtrate was concentrated. Theresidue was dissolved in a mixture of THF (0.5 mL) and LiOH (aq. 2N, 0.3mL, 0.6 mmol) and stirred at 60° C. for 15 h. The reaction mixture wasconcentrated and the residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 35-85% CH₃CN, 0.1% TFA)to give the title compound (36 mg, 0.051 mmol). MS (ES) 712.0 (M+H). ¹HNMR (400 MHz, DMSO-d₆): δ 7.74-7.68 (comp, 3H), 7.53 (d, J=7.0 Hz, 1H),7.26 (d, J=8.0 Hz, 1H), 6.794 (d, J=6.0 Hz, 1H), 6.75 (s, 2H), 4.08 (t,J=6.0 Hz, 2H), 3.98 (t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.65(t, J=8.0 Hz, 2H), 3.06 (t, J=8.0 Hz, 2H), 2.24 (s, 6H), 2.09-2.06 (m,2H), 2.03 (s, 3H), 1.93 (s, 3H), 1.76-1.72 (m, 2H).

Example 240 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-6-carboxylicacid I-240

The title compound was prepared (40 mg, 0.056 mmol) according toprocedures described in Example 239 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.20 mmol), methyl4-amino-1-methyl-1H-indole-6-carboxylate (49 mg, 0.24 mmol), DMAP (49mg, 0.40 mmol) and EDC (77 mg, 0.40 mmol). MS (ES) 712.0 (M+H). ¹H NMR(400 MHz, DMSO-d₆): δ 8.07 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.56-7.55(comp, 2H), 7.27 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 6.36 (d, J=4.0 Hz,1H), 4.12 (t, J=6.0 Hz, 2H), 3.98 (t, J=6.0 Hz, 2H), 3.90 (s, 3H), 3.78(s, 3H), 3.69 (t, J=6.0 Hz, 2H), 3.04 (t, J=8.0 Hz, 2H), 2.24 (s, 6H),2.09-2.06 (m, 2H), 2.03 (s, 3H), 1.93 (s, 3H), 1.76-1.72 (m, 2H).

Example 241 Preparation of6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-(pyridin-3-ylmethyl)-1H-indole-4-carboxylicacid I-241

The title compound was prepared (50 mg, 0.063 mmol) according toprocedures described in Example 239 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (70 mg, 0.14 mmol), methyl6-amino-1-(pyridin-3-ylmethyl)-1H-indole-4-carboxylate (47 mg, 0.168mmol), DMAP (34 mg, 0.28 mmol) and EDC (54 mg, 0.28 mmol). MS (ES) 789.0(M+H).

Example 242 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylicacid I-242

The title compound was prepared (35 mg, 0.044 mmol) according toprocedures described in Example 239 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (70 mg, 0.14 mmol), methyl4-amino-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylate (47 mg, 0.17mmol), DMAP (34 mg, 0.28 mmol) and EDC (54 mg, 0.28 mmol). MS (ES) 789.0(M+H).

Example 243 Preparation of6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-4-carboxylicacid I-243 Step A. Preparation of methyl6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1-(2-(dimethylamino)ethyl)-1H-indole-4-carboxylate

A solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (70 mg, 0.14 mmol), methyl6-amino-1-(2-(dimethylamino)ethyl)-1H-indole-4-carboxylate (40 mg, 0.154mmol), DMAP (34 mg, 0.28 mmol) and EDC (54 mg, 0.28 mmol) in DCM (2 mL)was stirred at rt for 16 h. The reaction mixture was concentrated, andthe residue was purified by silca gel flash chromatography (ISCO 0-10%MeOH/DCM gradient) to give the title compound (36 mg, 0.048 mmol). MS(ES) 743.1 (M+H).

Step B. Example 243

A solution of methyl6-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1-(2-(dimethylamino)ethyl)-1H-indole-4-carboxylate(36 mg, 0.048 mmol), 1,3-dibromopropane (15 μL, 0.15 mmol), Cs₂CO₃ (79mg, 0.24 mmol) in DMF (1.5 mL) was stirred at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was dissolved in a mixture of THF (1.5 mL) and LiOH (aq. 2N, 0.3mL, 0.6 mmol) and stirred at 40° C. for 15 h. The reaction mixture wasconcentrated, and the residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-80% CH₃CN, 0.1%NH₄OH) to give the title compound (5 mg, 0.007 mmol). MS (ES) 769.0(M+H).

Example 244 Preparation of6-(9-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-4-carboxylicacid I-244 Step A. Preparation of ethyl7-bromo-5-chloro-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate

Title compounds were prepared according to procedures described inExample 2 Step A and B using 2-bromo-4-chloroaniline. MS (ES) 402.0(M+H).

Step B. Preparation of ethyl7-bromo-5-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate

Title compound was prepared according to the procedure in Example 2 StepC using ethyl7-bromo-5-chloro-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate. MS(ES) 360.1 (M+H).

Step C. Preparation ethyl7-bromo-5-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate

Title compound was prepared as a colorless oil according to proceduresdescribed in Example 2 Step D using7-bromo-5-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate. MS (ES)498.0 (M+H).

Step D. Preparation of ethyl5-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

Title compound was prepared as a colorless oil according to proceduresdescribed in Example 28 Step A using7-bromo-5-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate. MS (ES)528.2 (M+H).

Step E. Preparation of5-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

Title compound was prepared as a colorless oil according to proceduresdescribed in Example 28 Step B using ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate.MS (ES) 500.2 (M+H).

Step F. Preparation of methyl6-(5-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1-methyl-1H-indole-4-carboxylate

A solution of5-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.100 mmol), methyl6-amino-1-methyl-1H-indole-4-carboxylate (25 mg, 0.12 mmol), DMAP (24mg, 0.20 mmol) and EDC (38 mg, 0.20 mmol) in DCM (2 mL) was stirred atrt for 16 h. The reaction mixture was concentrated, and the residue waspurified by silica gel flash chromatography (ISCO 0-10% MeOH/DCMgradient) to give the title compound (50 mg, 0.073 mmol). MS (ES) 686.0(M+H).

Step G. Example 244

A solution of methyl6-(5-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)-1-methyl-1H-indole-4-carboxylate(50 mg, 0.073 mmol), 1,3-dibromopropane (22 μL, 0.22 mmol), Cs₂CO₃ (119mg, 0.36 mmol) in DMF (1.5 mL) was stirred at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was dissolved in THF (0.5 mL) and LiOH (aq. 2N, 0.3 mL, 0.6mmol) and stirred at 60° C. for 15 h. The reaction mixture wasconcentrated, and the residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 35-90% CH₃CN, 0.1% TFA)to give the title compound (10 mg, 0.014 mmol). MS (ES) 712.0 (M+H).

Example 245 Preparation of4-(9-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-6-carboxylicacid I-245

The title compound was prepared (10 mg, 0.014 mmol) according toprocedures described in Example 244 Step F and G using5-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.10 mmol) and methyl4-amino-1-methyl-1H-indole-6-carboxylate (24 mg, 0.12 mmol). MS (ES)712.0 (M+H).

Example 246 Preparation of3-(9-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoicacid I-246

The title compound was prepared (25 mg, 0.038 mmol) according toprocedures described in Example 244 Step F and G using5-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.10 mmol) and methyl 3-amino-benzoate (18 mg, 0.12 mmol).MS (ES) 659.2 (M+H).

Example 247 Preparation of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(1-methyl-1H-indol-4-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-247

The title compound was prepared (27 mg, 0.040 mmol) according toprocedures described in Example 239 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.100 mmol) and 1-methyl-1H-indol-4-amine (18 mg, 0.12mmol). MS (ES) 668.1 (M+H).

Example 248 Preparation of8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(1-methyl-1H-indol-6-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-248

The title compound was prepared (14 mg, 0.021 mmol) according toprocedures described in Example 239 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.100 mmol) and 1-methyl-1H-indol-6-amine (16 mg, 0.11mmol). MS (ES) 668.1 (M+H), ¹H NMR (400 MHz, DMSO-d₆): δ 7.71 (d, J=8.0Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.37 (d, J=3.1 Hz, 1H),7.26 (d, J=8.0 Hz, 1H), 6.88 (dd, J=8.3, 1.7 Hz, 1H), 6.75 (s, 2H), 6.45(d, J=2.9 Hz, 1H), 4.07 (t, J=6.0 Hz, 2H), 3.97 (t, J=8.0 Hz, 2H), 3.79(s, 3H), 3.77 (s, 3H), 3.59 (t, J=6.0 Hz, 2H), 3.06 (t, J=6.0 Hz, 2H),2.25 (s, 6H), 2.09-2.06 (m, 2H), 2.03 (s, 3H), 1.92 (s, 3H), 1.82-1.77(m, 2H).

Example 249 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-ethyl-1H-indole-6-carboxylicacid I-249

The title compound was prepared (30 mg, 0.041 mmol) according toprocedures described in Example 239 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (60 mg, 0.12 mmol) and methyl4-amino-1-ethyl-1H-indole-6-carboxylate (31.4 mg, 0.144 mmol). MS (ES)726.1 (M+H).

Example 250 Preparation of5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-7-carboxylicacid I-250

The title compound was prepared (55 mg, 0.077 mmol) according toprocedures described in Example 239 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (80 mg, 0.160 mmol) and methyl5-amino-1-methyl-1H-indole-7-carboxylate (45 mg, 0.220 mmol). MS (ES)712.1 (M+H).

Example 251 Preparation of7-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-5-carboxylicacid I-251

The title compound was prepared (8.5 mg, 0.012 mmol) according toprocedures described in Example 239 Step A and B using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.20 mmol) and methyl7-amino-1-methyl-1H-indole-5-carboxylate (40.8 mg, 0.20 mmol). MS (ES)712.1 (M+H).

Example 252 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-6-carboxylicacid I-252 Step A. Preparation of methyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-6-carboxylate

A mixture of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(40 mg, 0.074 mmol),1-(tert-butyl) 6-methyl4-bromo-1H-indole-1,6-dicarboxylate (32 mg, 0.089 mmol), Xantphos (2.6mg, 4.5 μmol), Pd2(dba)₃ (1.4 mg, 1.5 μmol) and Cs₂CO₃ (36 mg, 0.11mmol) was degased for 10 min under Ar. 1,4-Dioxane (74.1 μl) was addedand the resulting mixture was heated to 110° C. for 16 h. The reactionmixture was cooled to rt, and TFA (100 μL) was added. The resultingreaction mixture was stirred for 2 h at 60° C. then concentrated. Theresidue was purified by the reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 40-90% CH₃CN, 0.1% TFA) to give title compound(12 mg, 0.017 mmol). MS (ES) 712.0 (M+H).

Step B. Example 252

A solution of methyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-6-carboxylate(12 mg, 0.017 mmol) in THF (0.1 mL) and LiOH (aq. 2N, 0.05 mL, 0.1 mmol)was heated at 40° C. for 2 d. The reaction mixture was concentrated andthe residue was purified by the reverse phase HPLC (Phenomenex GeminiC18, H₂O/CH₃CN gradient from 30-80% CH₃CN, 0.1% TFA) to give the titlecompound (5 mg, 0.007 mmol). MS (ES) 698.1 (M+H).

Example 253 Preparation of6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-4-carboxylicacid I-253

The title compound was prepared (5.2 mg, 0.007 mmol) according toprocedures described in Example 252 Step A and B using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(51 mg, 0.094 mmol) and 1-(tert-butyl) 4-methyl6-bromo-1H-indole-1,4-dicarboxylate (40 mg, 0.11 mmol). MS (ES) 698.1(M+H).

Example 254 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-3-formyl-1-methyl-1H-indole-6-carboxylicacid I-254 Step A. Preparation of methyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-3-formyl-1-methyl-1H-indole-6-carboxylate

Phosphorus oxychloride (7.70 μl, 0.083 mmol) was added to DMF (100 μL,1.29 mmol) at 0° C., and the resulting mixture was stirred for 15 min. Asolution of methyl4-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-6-carboxylate(40 mg, 0.055 mmol) in DMF (0.2 mL) was added at 0° C. The resultingmixture was warmed to 50° C. for 1 h. H₂O (0.1 mL) was added to quenchthe reaction. The solution was concentrated and the residue was purifiedby the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradientfrom 50-90% CH₃CN, 0.1% TFA) to give the title compound (38 mg, 0.050mmol). MS (ES) 754.0 (M+H).

Step B Example 254

The methyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-3-formyl-1-methyl-1H-indole-6-carboxylate(38 mg, 0.050 mmol) was dissolved in THF (0.2 ml) and LiOH (aq. 2N, 0.13mL, 0.26 mmol) and stirred at 60° C. for 15 h. The reaction mixture wasconcentrated, and the residue was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-80% CH₃CN, 0.1% TFA)to give the title compound (25 mg, 0.034 mmol). MS (ES) 740.1 (M+H).

Example 255 Preparation of3-chloro-4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-6-carboxylicacid I-255

To a stirred solution of methyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-6-carboxylate(40 mg, 0.055 mmol), NCS (7.7 mg, 0.058 mmol) was added and theresulting mixture was stirred at rt for 15 h. LiOH (aq. 2N, 0.14 mL,0.28 mmol) was added and the mixture was heated to 70° C. for 6 h. Thereaction mixture was concentrated, and the residue was purified by thereverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from40-90% CH₃CN, 0.1% TFA) to give the title compound (15 mg, 0.020 mmol).MS (ES) 746.2 (M+H).

Example 256 Preparation of3-bromo-4-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-6-carboxylicacid I-256

To a stirred solution of methyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-6-carboxylate(40 mg, 0.055 mmol), NBS (12 mg, 0.066 mmol) was added and the resultingmixture was stirred at rt for 15 h. LiOH (aq. 2N, 0.14 mL, 0.28 mmol)was added and the mixture was heated to 70° C. for 6 h. The reactionmixture was concentrated, and the residue was purified by the reversephase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 40-90% CH₃CN,0.1% TFA) to give the title compound (18 mg, 0.023 mmol). MS (ES) 792.1(M+H).

Example 257 Preparation of3-chloro-6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-4-carboxylicacid I-257

The title compound was prepared (18 mg, 0.024 mmol) according toprocedures described in Example 225 using methyl6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-4-carboxylate(40 mg, 0.055 mmol), NCS (7.35 mg, 0.055 mmol). MS (ES) 748.2 (M+H). ¹HNMR (400 MHz, DMSO-d₆): δ 7.73-7.69 (comp, 3H), 7.40 (s, 1H), 7.26 (d,J=8.0 Hz, 1H), 6.74 (s, 2H), 4.09-4.06 (m, 2H), 3.98 (t, J=8.0 Hz, 2H),3.80 (s, 3H), 3.78 (s, 3H), 3.64 (t, J=6.0 Hz, 2H), 3.05 (t, J=8.0 Hz,2H), 2.24 (s, 6H), 2.10-2.06 (m, 2H), 2.03 (s, 3H), 1.92 (s, 3H),1.82-1.76 (m, 2H).

Example 258 Preparation of3-bromo-6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-4-carboxylicacid I-258

The title compound was prepared (5 mg, 0.006 mmol) according toprocedures described in Example 226 using methyl6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-4-carboxylate(40 mg, 0.055 mmol), NBS (10 mg, 0.058 mmol). MS (ES) 792.1 (M+H).

Example 259 Preparation ofN-(1-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)piperidin-4-yl)-3-phenoxybenzamideI-259 Step A. Preparation of(4-aminopiperidin-1-yl)(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indol-2-yl)methanone2,2,2-trifluoroacetate

To a stirred solution of tert-butyl(1-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carbonyl)piperidin-4-yl)carbamate(0.037 mmol) in DCM (1 mL) was added TFA (0.2 mL). The reaction wasstirred for 2 h then the volatiles were removed in vacuo to give thecrude title product which was directly used in subsequent step withoutfurther purification.

Step B. Example 259

The title compound was prepared according to the procedure used inExample 40 by substituting(4-aminopiperidin-1-yl)(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indol-2-yl)methanone2,2,2-trifluoroacetate for aniline. ¹H NMR (CDCl₃, 400 MHz, 25° C.):8.41 (br s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.41-7.33 (m, 6H), 7.29 (m,1H), 7.27 (t, J=8.0 Hz 1H), 7.14 (m, 3H), 7.01 (d, J=8.0 Hz, 2H), 6.61(s, 2H), 5.92 (m, 1H), 4.33-4.18 (m, 3H), 3.90 (t, J=6.0 Hz, 2H), 3.46(m, 2H), 3.55 (br t, J=6.0 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 2.34 (s,6H), 2.24-2.19 (m, 2H), 2.02 (t, J=8.0 Hz, 2H), 2.31 (s, 6H), 2.18-2.09(m, 4H), 1.53-1.43 (m, 2H); MS (ES) 636.3 (M+H).

Example 260 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((6-chloropyridin-3-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-260

The title compound was prepared according to the procedure used inExample 40 using the requisite amine. MS (ES) 636.3 (M+H).

Example 261 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((6-(3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-261

To a microwave reaction vial was added cesium carbonate (0.068 mmol),3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((6-chloropyridin-3-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide(0.034 mmol), palladium acetate (0.0034 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0042 mmol), and astir bar. This mixture was suspended in dioxane (0.05 M) for theaddition of 1,2,3,4-tetrahydroisoquinoline (0.037 mmol). The microwavevial was then crimped and immediately transferred to the microwavereactor for heating at 100° C. for a period of 35 minutes. The reactionwas filtered through Celite and volatiles were removed in vacuo. Theresidue was then dissolved in 1 mL of a 1:1 mix of acetonitrile andmethanol and was purified by reverse phase preparatory HPLC (H₂O/CH₃CNgradient to 95% CH₃CN 0.1% TFA) to yield the title compound as a whitesolid. MS (ES) 687.1 (M+H).

Example 262 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((2-chloropyridin-4-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-262

The title compound was prepared according to the procedure used inExample 40 using the requisite amine. MS (ES) 636.3 (M+H).

Example 263 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((2-(3,4-dihydroisoquininolin-2(1H)-yl)pyridin-4-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-263

The title compound was prepared according to the procedure used inExample 261 by substituting3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((2-chloropyridin-4-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamidefor3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((6-chloropyridin-3-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide.MS (ES) 687.1 (M+H).

Example 264 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-(trifluoromethoxy)benzyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-264

The title compound was prepared according to the procedure used inExample 48 by substituting (3-(trifluoromethoxy)phenyl)methanamine fortert-butyl piperidin-4-ylcarbamate. MS (ES) 639.0 (M+H).

Example 265 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-methyl-5-(trifluoromethoxy)benzyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide265

The title compound was prepared according to the procedure used inExample 48 by substituting(3-methyl-5-(trifluoromethoxy)phenyl)methanamine for tert-butylpiperidin-4-ylcarbamate. MS (ES) 653.1 (M+H).

Example 266 Preparation of ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylateI-266

To a stirred solution of EDC (0.502 mmol), HOBT (0.033 mmol),3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (0.335 mmol) in DCM (0.1M) and TEA (1.34 mmol) was added ethyl5-(aminomethyl)furan-2-carboxylate hydrochloride (0.368 mmol). Thereaction mixture was allowed to stir for 15 hours. Upon completion thevolatiles were removed via rotary evaporation and the remaining materialslurried in 1 mL of 1:1 mix of acetonitrile and methanol. The slurry wasfiltered and the filtrate was purified by reverse phase preparatory HPLC(H₂O/CH₃CN gradient to 95% CH₃CN 0.1% TFA) to yield the title compoundas a white solid. MS (ES) 617.1 (M+H).

Example 267 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylicacid I-267

The title compound was prepared according to the procedure used inExample 57 by substituting ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.¹H NMR (d6-DMSO, 400 MHz, 25° C.): 10.56 (s, 1H), 8.88 (m, 1H), 7.59 (d,J=8.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 7.15-7.00 (m, 2H), 6.76 (s, 2H),6.48 (m, 1H), 4.54 (d, J=8.0 Hz, 2H), 3.77 (s, 3H), 3.25 (t, J=6.0 Hz,2H), 2.27 (s, 6H), 2.09 (s, 3H), 2.06-2.01 (m, 5H), MS (ES) 589.0 (M+H).

Example 268 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((5-(hydroxymethyl)furan-2-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-268

To a stirred solution of ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate(0.032 mmol) in THF (0.1M) at 0° C. was added 2M Lithium borohydridesolution in THF (0.096 mmol). The reaction was allowed to slowly warm toroom temperature and stir for an additional 15 h. The mixture was thencooled to 0° C. and acidified to pH 6 with 3N aqueous HCl. The mixturewas extracted with ethyl acetate and the organic layer washed withbrine, dried over sodium sulfate can concentrated via rotaryevaporation. The solid was then dissolved in 1 mL of a 1:1 mix ofacetonitrile and methanol and was purified by reverse phase preparatoryHPLC (H₂O/CH₃CN gradient to 95% CH₃CN 0.1% TFA) to yield the titlecompound as a white solid. MS (ES) 575.1 (M+H).

Example 269 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N,1-dimethyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylicacid I-269

To a stirred solution of ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate(0.043 mmol) in THF was added sodium hydride (0.43 mmol) at 0° C. Afteraddition, the mixture was allowed to stir at room temperature for 30minutes before the addition of iodomethane (0.43 mmol). After one hourthe reaction was reverse-quenched into a mixture of 3M HCl and DCM. Theaqueous phase was extracted with DCM, washed with brine, dried overmagnesium sulfate and concentrated via rotary evaporation. The residuewas then dissolved in 1 mL of a 1:1 mix of acetonitrile and methanol andwas purified by reverse phase preparatory HPLC (H₂O/CH₃CN gradient to95% CH₃CN 0.1% TFA) to yield the title compound as a white solid. MS(ES) 617.1 (M+H).

Example 270 Preparation of(5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carbonyl)-L-isoleucineI-270 Step A. Preparation of methyl(5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carbonyl)-L-isoleucinate

To a stirred solution of EDC (0.043 mmol), HOBT (0.003 mmol),5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylicacid (0.028 mmol) in DCM (0.1M) and TEA (0.115 mmol) was added methylL-isoleucinate hydrochloride (0.032 mmol). The reaction mixture wasallowed to stir for 15 h. Upon completion the volatiles were removed viarotary evaporation and the remaining material adsorbed onto silica gel.The material was isolated via silica gel chromatography using a gradientup to 5% methanol in DCM to yield the title compound as a foam. MS (ES)716.1 (M+H).

Step B. Example 270

Title compound was prepared according to the procedure used in Example57 by substituting methyl(5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carbonyl)-L-isoleucinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 702.1 (M+H).

Example 271 Preparation of(5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carbonyl)-L-phenylalanineI-271 Step A. Preparation of methyl(5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carbonyl)-L-phenylalaninate

The title compound was prepared according to the procedure used inExample 270 Step A by substituting methyl L-phenylalaninatehydrochloride for methyl L-isoleucinate hydrochloride. MS (ES) 750.1(M+H).

Step B. Example 271

The title compound was prepared according to the procedure used inExample 270 Step B by substituting methyl(5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carbonyl)-L-phenylalaninatefor methyl(5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carbonyl)-L-isoleucinate.MS (ES) 736.0 (M+H).

Example 272 Preparation of methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-methylfuran-3-carboxylateI-272

The title compound was prepared according to the procedure used inExample 266 by substituting methyl5-(aminomethyl)-2-methylfuran-3-carboxylate hydrochloride for ethyl5-(aminomethyl)furan-2-carboxylate hydrochloride. MS (ES) 617.1 (M+H).

Example 273 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-methylfuran-3-carboxylicacid I-273

The title compound was prepared according to the procedure used inExample 57 by substituting methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-methylfuran-3-carboxylatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 603.0 (M+H).

Example 274 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N,1-dimethyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-methylfuran-3-carboxylicacid I-274

Title compound was prepared according to the procedure used in Example269 by substituting methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-methylfuran-3-carboxylatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 617.1 (M+H).

Example 275 Preparation ofN-((4-(benzylcarbamoyl)-5-methylfuran-2-yl)methyl)-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-275

To a stirred solution of EDC (0.082 mmol), HOBT (0.005 mmol),5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-methylfuran-3-carboxylicacid (0.055 mmol) in DCM (0.1M) and TEA (0.219 mmol) was added benzylamine (0.060 mmol). The reaction mixture was allowed to stir for 15hours. Upon completion the volatiles were removed via rotary evaporationand the residue was then dissolved in 1 mL of a 1:1 mix of acetonitrileand methanol and was purified by reverse phase preparatory HPLC(H₂O/CH₃CN gradient to 95% CH₃CN 0.1% TFA) to yield the title compoundas a white solid. MS (ES) 692.1 (M+H).

Example 276 Preparation of methyl2-chloro-6-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)isonicotinateI-276

The title compound was prepared according to the procedure used inExample 266 by substituting methyl 2-(aminomethyl)-6-chloroisonicotinatefor ethyl 5-(aminomethyl)furan-2-carboxylate hydrochloride. MS (ES)648.0 (M+H).

Example 277 Preparation of2-chloro-6-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)isonicotinicacid I-277

The title compound was prepared according to the procedure used inExample 57 by substituting2-chloro-6-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)isonicotinicacid for ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 633.2 (M+H).

Example 278 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((6-((2,3-dihydro-1H-inden-2-yl)amino)-4-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-2-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-278

To a microwave compatible vessel containing methyl2-chloro-6-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)isonicotinate(0.055 mmol) and a stir bar was added 2,3-dihydro-1H-inden-2-amine(0.139 mmol). The vessel was sealed and placed in the microwave for 1 hat 225° C. Upon completion the reaction was slurried in 1 mL of 1:1 mixof acetonitrile and methanol. The slurry was filtered and the filtratewas purified by reverse phase preparatory HPLC (H₂O/CH₃CN gradient to95% CH₃CN-0.1% TFA) to yield the title compound an oil. MS (ES) 846.1(M+H).

Example 279 Preparation of ethyl2-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)isonicotinateI-279

The title compound was prepared according to the procedure used inExample 266 by substituting ethyl 2-(aminomethyl)isonicotinatehydrochloride for ethyl 5-(aminomethyl)furan-2-carboxylatehydrochloride. MS (ES) 628.0 (M+H).

Example 280 Preparation of2-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)isonicotinicacid I-280

The title compound was prepared according to the procedure used inExample 57 by substituting ethyl2-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)isonicotinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 600.1 (M+H).

Example 281 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-((4-(hydroxymethyl)pyridin-2-yl)methyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-281

The title compound was prepared according to the procedure used inExample 268 by substituting ethyl2-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)isonicotinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.¹H NMR (d6-DMSO, 400 MHz, 25° C.): 10.60 (s, 1H), 9.07 (m, 1H), 8.63 (d,J=8.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.12-7.02 (m, 2H), 6.76 (s, 2H), 4.72(m, 2H), 4.67 (s, 2H), 3.97 (m, 2H), 3.77 (s, 3H), 3.22 (m, 2H), 2.27(s, 6H), 2.11 (s, 3H), 2.06-1.98 (m, 5H); MS (ES) 586.0 (M+H).

Example 282 Preparation of2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinicacid I-282 Step A. Preparation of methyl2-(3,4-dihydroisoquinolin-2(1H)-yl)-6-((1,3-dioxoisoindolin-2-yl)methyl)isonicotinate

To a microwave reaction vial was added cesium carbonate (0.151 mmol),methyl 2-chloro-6-((1,3-dioxoisoindolin-2-yl)methyl)isonicotinate (0.076mmol), palladium acetate (0.0076 mmol),2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0095 mmol), and astir bar. This mixture was suspended in dioxane (0.05 M) for theaddition of 1,2,3,4-tetrahydroisoquinoline (0.083 mmol). The microwavevial was then crimped and immediately transferred to the microwavereactor for heating at 110° C. for a period of 90 minutes. Uponcompletion the reaction was filtered through Celite and volatiles wereremoved in vacuo. The residue was then adsorbed onto silica gel. Thematerial was isolated via silica gel chromatography using a gradient upto 50% ethyl acetate in hexanes to yield the Title compound white solid.MS (ES) 428.1 (M+H).

Step B. Preparation of methyl2-(aminomethyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate

To a stirred solution of methyl2-(3,4-dihydroisoquinolin-2(1H)-yl)-6-((1,3-dioxoisoindolin-2-yl)methyl)isonicotinate(0.035 mmol) in methanol (0.05 M) was added hydrazine hydrate (0.070mmol) at room temperature. Upon completion the volatiles were removed invacuo, the residue was slurried in 1 mL of 1:1 mix of acetonitrile andmethanol. The slurry was filtered and the filtrate was purified byreverse phase preparatory HPLC (H₂O/CH₃CN gradient to 95% CH₃CN 0.1%TFA) to yield the title compound as a yellow glass. MS (ES) 298.2 (M+H).

Step C. Preparation of methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate

To a stirred solution of EDC (0.015 mmol), HOBT (0.001 mmol),6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (0.01 mmol) in DCM (0.1M) and TEA (0.04 mmol) was added methyl2-(aminomethyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate. Thereaction mixture was allowed to stir for 15 hours. Upon completion thevolatiles were removed via rotary evaporation and the residue was thenadsorbed onto silica gel. The material was isolated via silica gelchromatography using a gradient up to 10% methanol in DCM to yieldmethyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate.MS (ES) 779.1 (M+H).

Step D. Example 282

Title compound was prepared according to the procedure used in Example57 by substituting methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 765.0 (M+H).

Example 283 Preparation of2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(isopentylamino)isonicotinicacid I-283 Step A. Preparation of methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(isopentylamino)isonicotinate

The title compound was prepared according to the procedure used inExample 282 Step A by substituting 3-methylbutan-1-amine for1,2,3,4-tetrahydroisoquinoline MS (ES) 382.2 (M+H).

Step B. Preparation of methyl2-(aminomethyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate

The title compound was prepared according to the procedure used inExample 282 Step B by substituting methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(isopentylamino)isonicotinate formethyl 2-(aminomethyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate.MS (ES) 252.3 (M+H).

Step C. Preparation of methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(isopentylamino)isonicotinate

The title compound was prepared according to the procedure used inExample 282 Step C by substituting methyl2-(aminomethyl)-6-(isopentylamino)isonicotinate for methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate.MS (ES) 733.0 (M+H).

Step D. Example 283

The title compound was prepared according to the procedure used inExample 57 by substituting methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(isopentylamino)isonicotinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 719.1 (M+H).

Example 284 Preparation of2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinicacid I-284 Step A. Preparation of methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(piperazin-1-yl)isonicotinate

Title compound was prepared according to the procedure used in Example282 Step A by substituting piperazine for1,2,3,4-tetrahydroisoquinoline. MS (ES) 381.1 (M+H).

Step B. Preparation of methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinate

To a stirred solution of methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(piperazin-1-yl)isonicotinate(0.050 mmol) in DCM (0.1M) and TEA (0.152 mmol) was added isovalerylchloride (0.10 mmol). The reaction mixture was allowed to stir for 15 hat rt. Upon completion the volatiles were removed via rotary evaporationand the material used in the next step without further purification. MS(ES) 465.1 (M+H).

Step C. Preparation of methyl2-(aminomethyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinate

To a stirred solution of methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinate(0.035 mmol) in methanol (0.05 M) was added hydrazine hydrate (0.070mmol) at room temperature. Upon completion the volatiles were removed invacuo, the residue was partitioned in DCM and saturated sodiumbicarbonate. The aqueous phase was extracted with DCM, washed withbrine, dried over magnesium sulfate and concentrated via rotaryevaporation. The material used in the next step without furtherpurification. MS (ES) 335.2 (M+H).

Step D. Preparation of methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinate

The title compound was prepared according to the procedure used inExample 282 Step C by substituting methyl2-(aminomethyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinate formethyl 2-(aminomethyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate.MS (ES) 816.3 (M+H).

Step E. Example 284

The title compound was prepared according to the procedure used inExample 57 by methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 802.0 (M+H).

Example 285 Preparation of2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(4-isopentylpiperazin-1-yl)isonicotinicacid I-285 Step A. Preparation of methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(piperazin-1-yl)isonicotinate

The title compound was prepared according to the procedure used inExample 282 Step A by substituting piperazine for1,2,3,4-tetrahydroisoquinoline. MS (ES) 381.1 (M+H).

Step B. Preparation of methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(4-isopentylpiperazin-1-yl)isonicotinate

To a stirred solution of product from Step A (0.050 mmol) in DCM (0.1M)and TEA (0.152 mmol) was added isovaleraldehyde (0.101 mmol). Thereaction mixture was allowed to stir for 30 minutes at room temperaturebefore the addition of sodium triacetoxyborohydride. Upon completion thereaction was quenched with saturated sodium bicarbonate, the aqueousphase was extracted with DCM, washed with brine, dried over magnesiumsulfate and concentrated via rotary evaporation. The material was usedin the next step without further purification. MS (ES) 451.2 (M+H).

Step C. Preparation of methyl2-(aminomethyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinate

To a stirred solution of methyl2-((1,3-dioxoisoindolin-2-yl)methyl)-6-(4-isopentylpiperazin-1-yl)isonicotinate(0.035 mmol) in methanol (0.05 M) was added hydrazine hydrate (0.070mmol) at room temperature. Upon completion the volatiles were removed invacuo, the residue was partitioned in DCM and saturated sodiumbicarbonate. The aqueous phase was extracted with DCM, washed withbrine, dried over magnesium sulfate and concentrated via rotaryevaporation. The material used in the next step without furtherpurification. MS (ES) 321.2 (M+H).

Step D. Preparation of methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinate

The title compound was prepared according to the procedure used inExample 282 Step C by methyl2-(aminomethyl)-6-(4-isopentylpiperazin-1-yl)isonicotinate for methyl2-(aminomethyl)-6-(3,4-dihydroisoquinolin-2(1H)-yl)isonicotinate. MS(ES) 802.3 (M+H).

Step E. Example 285

The title compound was prepared according to the procedure used inExample 57 by substituting methyl2-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-6-(4-(3-methylbutanoyl)piperazin-1-yl)isonicotinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 802.0 (M+H).

Example 286 Preparation of(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycineI-286 Step A. Preparation of methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycinate

The title compound was prepared according to the procedure used inExample 40 using methyl glycinate hydrochloride in place of aniline. MS(ES) 537.3 (M+H).

Step B. Example 286

The title compound was prepared according to the procedure used inExample 57 by substituting methyl.(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 523.0 (M+H).

Example 287 Preparation of methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycylglycinateI-287

To a stirred solution of EDC (0.072 mmol), HOBT (0.005 mmol),(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycine(0.048 mmol) in DCM (0.1M) and TEA (0.191 mmol) was added methylglycinate hydrochloride (0.057 mmol). The reaction mixture was allowedto stir for 15 h. Upon completion the volatiles were removed via rotaryevaporation and the remaining material adsorbed onto silica gel. Thematerial was isolated via silica gel chromatography using a gradient upto 10% methanol in DCM to yield the Title compound as a foam. MS (ES)594.3 (M+H).

Example 288 Preparation of methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycyl-L-phenylalaninateI-288

The title compound was prepared according to the procedure used inExample 328 by substituting methyl L-phenylalaninate hydrochloride formethyl glycinate hydrochloride. MS (ES) 684.1 (M+H).

Example 289 Preparation of methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycyl-L-leucinateI-289

The title compound was prepared according to the procedure used inExample 328 by substituting methyl L-leucinate hydrochloride for methylglycinate hydrochloride. MS (ES) 650.1 (M+H).

Example 290 Preparation of(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycylglycineI-290

The title compound was prepared according to the procedure used inExample 57 by substituting methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycylglycinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 580.0 (M+H).

Example 291 Preparation of(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycyl-L-phenylalanineI-291

The title compound was prepared according to the procedure used inExample 57 by substituting methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycyl-L-phenylalaninatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 670.1 (M+H).

Example 292 Preparation of(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycyl-L-leucineI-292

The title compound was prepared according to the procedure used inExample 57 by substituting methyl(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)glycyl-L-leucinatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 636.1 (M+H).

Example 293 Preparation of5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)furan-3-carboxylicacid I-293 Step A. Preparation of methyl5-((1,3-dioxoisoindolin-2-yl)methyl)-2-methylfuran-3-carboxylate

To a microwave compatible vessel containing methyl5-(aminomethyl)-2-methylfuran-3-carboxylate hydrochloride (1.2 mmol) anda stir bar was added isobenzofuran-1,3-dione (1.2 mmol). The vessel wassealed and placed in the microwave for 30 min at 150° C. Upon completionthe material was partitioned in DCM and saturated sodium bicarbonate.The aqueous phase was extracted with DCM, washed with brine, dried overmagnesium sulfate and concentrated via rotary evaporation. The materialused in the next step without further purification. MS (ES) 300.1 (M+H).

Step B. Preparation of methyl2-(bromomethyl)-5-((1,3-dioxoisoindolin-2-yl)methyl)furan-3-carboxylate

To a solution of methyl5-((1,3-dioxoisoindolin-2-yl)methyl)-2-methylfuran-3-carboxylate (0.84mmol) in chlorobenzene (0.1M) was added NBS (0.92 mmol) and AIBN (0.17mmol). The reaction mixture was allowed to stir for 15 h at 90° C. Uponcompletion the volatiles were removed via rotary evaporation and theresidue was partitioned in DCM and saturated sodium bicarbonate. Theaqueous phase was extracted with DCM, washed with brine, dried overmagnesium sulfate and adsorbed onto silica gel. The material wasisolated via silica gel chromatography using a gradient up to 25% ethylacetate in hexanes to yield the title compound. MS (ES) 399.9 (M+Na).

Step C. Preparation methyl2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((1,3-dioxoisoindolin-2-yl)methyl)furan-3-carboxylate

To a stirred solution of methyl2-(bromomethyl)-5-((1,3-dioxoisoindolin-2-yl)methyl)furan-3-carboxylate(0.20 mmol) in DCM (0.2 M) and TEA (0.60 mmol) was added1,2,3,4-tetrahydroisoquinoline (0.25 mmol) at rt. After 1 h, thereaction adsorbed onto silica gel. The material was isolated via silicagel chromatography using a gradient up to 5% methanol in DCM to yieldthe title compound. MS (ES) 431.1 (M+H).

Step D. Preparation of methyl5-(aminomethyl)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)furan-3-carboxylate

To a stirred solution of methyl2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((1,3-dioxoisoindolin-2-yl)methyl)furan-3-carboxylate(0.070 mmol) in methanol (0.05 M) was added hydrazine hydrate (0.077mmol) at room temperature. After 2 h, the volatiles were removed invacuo, the residue was slurried in 1 mL of 1:1 mix of acetonitrile andmethanol. The slurry was filtered and the filtrate was purified by thereverse phase preparatory HPLC (H₂O/CH₃CN gradient to 25% CH₃CN 0.1%TFA) to yield the title compound as a white solid. MS (ES) 301.2 (M+H).

Step E. Preparation of methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)furan-3-carboxylate

The title compound was prepared according to the procedure used inExample 266 by substituting methyl5-(aminomethyl)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)furan-3-carboxylatefor ethyl 5-(aminomethyl)furan-2-carboxylate hydrochloride. MS (ES)748.3 (M+H).

Step E. Example 293

The title compound was prepared according to the procedure used inExample 57 by substituting methyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)furan-3-carboxylatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 734.1 (M+H).

Example 294 Preparation of2-(2-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)ethyl)benzoicacid I-294 Step A. Preparation of methyl2-(2-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)ethyl)benzoate

To a stirred solution of EDC (0.096 mmol), HOBT (0.007 mmol),6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (0.064 mmol) in DCM (0.1M) and TEA (0.255 mmol) was added methyl2-(2-aminoethyl)benzoate. The reaction mixture was allowed to stir for15 h. Upon completion the volatiles were removed via rotary evaporationand the residue was then adsorbed onto silica gel. The material wasisolated via silica gel chromatography using a gradient up to 10%methanol in DCM to yield the title compound. MS (ES) 661.0 (M+H).

Step B. Preparation of methyl2-(2-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)ethyl)benzoate

To a stirred solution of methyl2-(2-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)ethyl)benzoate(0.038 mmol) in DMF (0.1 M) was added cesium carbonate (0.19 mmol)followed by 1,2-dibromopropane at room temperature. After 15 minutes,the reaction was heated to 60° C. for a period of 15 h. The reactionmixture was filtered and partitioned between ethyl acetate and water.The aqueous phase was extracted with ethyl acetate. The combinedorganics were diluted with hexanes, washed with water, followed bybrine, dried over magnesium sulfate and concentrated via rotaryevaporation to give the crude title product, which was taken onto thenext step without further purification. MS (ES) 701.1 (M+H).

Step C. Example 294

The title compound was prepared according to the procedure used inExample 57 by substituting methyl2-(2-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)ethyl)benzoatefor ethyl5-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxamido)methyl)furan-2-carboxylate.MS (ES) 687.1 (M+H).

Example 295 Preparation of2-(4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-7-yl)-3,5-dimethyl-1H-pyrazol-1-yl)aceticacid I-295 Step A. Preparation of ethyl7-(1-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate

To a microwave reaction vial was added tert-butyl2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate(0.446 mmol), ethyl7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate(0.491 mmol), dioxane (0.6 M) and an aqueous solution of 2N potassiumcarbonate (0.3 M), and a stir bar. Immediately before placing the vesselin the microwave, tetrakis(triphenylphosphine)palladium (0.026 mmol) wasadded and the vial crimped for heating at 115° C. for a period of 60min. The reaction was then neutralized to a pH of 7 for extraction withethyl acetate. The combined organics were then washed with brine, driedover magnesium sulfate, filtered and volatiles were removed in vacuo.The material was then adsorbed onto silica gel for isolation via silicagel chromatography using a gradient up to 50% ethyl acetate in hexanesto yield the title compound as a white foam. ¹H NMR (d6-DMSO 400 MHz,25° C.): 10.67 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.2 (d, J=8.0 Hz, 1H),6.76 (s, 2H), 4.29 (m, 2H), 3.99 (m, 2H), 3.18 (m, 2H), 2.28 (s, 6H),2.04 (m, 2H), 1.93 (s, 3H), 1.91 (s, 3H), 1.45 (s, 9H), 1.30 (t, J=6.0Hz, 3H), 1.08 (s, 6H); MS (ES) 628.0 (M+H).

Step B. Preparation of ethyl7-(1-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate

To a stirred solution of ethyl7-(1-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate(0.13 mmol) and tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide(0.19 mmol) in DMF (0.1 M) was added NaH as a 60% dispersion in mineraloil (0.377 mmol) at rt. The reaction was allowed to stir for 15 h beforequenching with a 10% citric acid solution. After 1 h, ethyl acetate wasadded and the layers separated. The aqueous phase was extracted twicewith ethyl acetate. The combined organics were diluted with hexanesuntil slightly cloudy and then washed with water twice, then brine. Theorganics were then dried over magnesium sulfate, filtered and thevolatiles were removed in vacuo. The isolated crude title compound wasused in the next step without further purification. MS (ES) 785.1 (M+H).

Step C. Preparation of2-(4-(1-(3-aminopropyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(ethoxycarbonyl)-1H-indol-7-yl)-3,5-dimethyl-1H-pyrazol-1-yl)aceticacid

To a stirred solution of ethyl7-(1-(2-(tert-butoxy)-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate(0.13 mmol) in THF (0.1 M) was added a solution of 4M HCl in dioxane(0.8 mmol) and the reaction allowed to stir for 15 h before removing thevolatiles via rotary evaporation. The residue was then partitioned in amixture of DCM and saturated sodium bicarbonate (aq), the aqueous phasewas extracted with DCM twice. The combined organics were washed withbrine, dried over magnesium sulfate, filtered and evaporated to dryness.The crude title compound was used in the next step without furtherpurification. MS (ES) 685.1 (M+H).

Step D. Example 295

To a stirred solution of2-(4-(1-(3-aminopropyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(ethoxycarbonyl)-1H-indol-7-yl)-3,5-dimethyl-1H-pyrazol-1-yl)aceticacid (0.073 mmol) in methanol (0.05 M) was added potassium carbonate(0.182 mmol). The reaction was then heated to 60° C. as a sealed systemfor a period of 14 hours. The solvent was removed via rotary evaporationand the crude material was partitioned between DCM and water. Theaqueous phase was neutralized to a pH of 7 with an aqueous solution of1M HCL. The layers were separated, the water layer was extracted withDCM three times, the combined organics were washed with brine, driedover magnesium sulfate, filtered and evaporated to dryness. The crudematerial was then slurried in 1 mL of 1:1 mix of acetonitrile andmethanol. The slurry was filtered and the filtrate was purified byreverse phase preparatory HPLC (H₂O/CH₃CN gradient from 40% to 95% CH₃CN0.1% TFA) to yield the title compound. MS (ES) 583.0 (M+H).

Example 296 Preparation of3-bromo-5-((1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-296

To a stirred solution of11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(0.065 mmol) in DMF (0.1 M) was added sodium hydride as a 60% dispersionin mineral oil (0.196 mmol) at room temperature and the reaction allowedto stir for 30 minutes. After the allotted time, methyl3-bromo-5-(bromomethyl)benzoate was added at room temperature and thereaction allowed to stir for 15 hours. The reaction was then quenchedwith an aqueous solution of 3M HCL followed by the addition of ethylacetate. The layers were separated, the water layer was extracted withethyl acetate three times, the combined organics were washed with brine,dried over magnesium sulfate, filtered and evaporated to dryness. Thecrude material was then slurried in 1 mL of 1:1 mix of acetonitrile andmethanol. The slurry was filtered and the filtrate was purified byreverse phase preparatory HPLC (H₂O/CH₃CN gradient from 50% to 95% CH₃CN0.1% TFA) to yield the title compound. MS (ES) 718.9 (M+H).

Example 297 Preparation of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-methylbenzoicacid I-297

Title compound was prepared according to the procedure used in Example296 by substituting methyl 3-(bromomethyl)-5-methylbenzoate and8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor methyl 3-bromo-5-(bromomethyl)benzoate and11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 687.0 (M+H).

Example 298 Preparation of2-chloro-6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)isonicotinicacid I-298

Title compound was prepared according to the procedure used in Example296 by substituting methyl 2-(bromomethyl)-6-chloroisonicotinate and8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor methyl 3-bromo-5-(bromomethyl)benzoate and11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 708.2 (M+H).

Example 299 Preparation of3-bromo-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-299

Title compound was prepared according to the procedure used in Example296 by substituting8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor 1μl-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-μH-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 752.9 (M+H).

Example 300 Preparation of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-(isopentyloxy)benzoicacid I-300

Title compound was prepared according to the procedure used in Example296 by substituting methyl 3-(bromomethyl)-5-(isopentyloxy)benzoate and8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor methyl 3-bromo-5-(bromomethyl)benzoate and11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 759.1 (M+H).

Example 301 Preparation of3-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-((4-methylpentyl)oxy)benzoicacid I-301

Title compound was prepared according to the procedure used in Example296 by substituting methyl3-(bromomethyl)-5-((4-methylpentyl)oxy)benzoate and8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor methyl 3-bromo-5-(bromomethyl)benzoate and11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 773.1 (M+H).

Example 302 Preparation of2-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-(isopentyloxy)isonicotinicacid I-302

Title compound was prepared according to the procedure used in Example296 by substituting methyl 2-(bromomethyl)-6-(isopentyloxy)isonicotinateand8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor methyl 3-bromo-5-(bromomethyl)benzoate and11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 760.1 (M+H).

Example 303 Preparation of2-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-6-((4-methylpentyl)oxy)isonicotinicacid I-303

Title compound was prepared according to the procedure used in Example296 by substituting methyl2-(bromomethyl)-6-((4-methylpentyl)oxy)isonicotinate and8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor methyl 3-bromo-5-(bromomethyl)benzoate and11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 774.1 (M+H).

Example 304 Preparation of2-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)aceticacid I-304

Title compound was prepared according to the procedure used in Example296 by substituting tert-butyl 2-bromoacetate and8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor methyl 3-bromo-5-(bromomethyl)benzoate and11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 597.1 (M+H).

Example 305 Preparation of(2-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)acetyl)-L-phenylalanineI-305

To a stirred solution of EDC (0.018 mmol), HOBT (0.001 mmol),2-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)aceticacid (0.012 mmol) in DCM (0.1M) and TEA (0.047 mmol) was added methylL-phenylalaninate hydrochloride (0.013 mmol). The reaction mixture wasallowed to stir for 20 hours. Upon completion the volatiles were removedvia rotary evaporation and the material was dissolved in THF (0.5 mL)and treated with aqueous 2M LiOH (0.2 mL). The reaction was thenquenched with an aqueous solution of 3M HCL followed by the addition ofethyl acetate. The layers were separated, the water layer was extractedwith ethyl acetate three times, the combined organics were washed withbrine, dried over magnesium sulfate, filtered and evaporated to dryness.The crude material was then slurried in 0.5 mL of 1:1 mix ofacetonitrile and methanol. The slurry was filtered and the filtrate waspurified by reverse phase preparatory HPLC (H₂O/CH₃CN gradient from 50%to 95% CH₃CN 0.1% TFA) to yield the title compound. MS (ES) 744.0 (M+H).

Example 306 Preparation of5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(31H)-yl)methyl)-4′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid I-306

To a microwave reaction vial was added3-bromo-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid (0.041 mmol), (4-hydroxyphenyl)boronic acid (0.049 mmol), dioxane(0.1M) and an aqueous solution of 2N potassium carbonate (0.1 M), and astir bar. Immediately before placing the vessel in the microwave,tetrakis(triphenylphosphine)palladium (0.026 mmol) was added and thevial crimped for heating at 125° C. for a period of 60 minutes. Thereaction was then acidified to a pH of 7 with 1M HCl (aq) for extractionwith ethyl acetate. The aqueous phase was extracted three times, thecombined organics were then washed with brine, dried over magnesiumsulfate, filtered and volatiles were removed in vacuo. The crudematerial was then slurried in 0.5 mL of 1:1 mix of acetonitrile andmethanol. The slurry was filtered and the filtrate was purified byreverse phase preparatory HPLC (H₂O/CH₃CN gradient from 50% to 95% CH₃CN0.1% TFA) to yield the title compound. MS (ES) 765.0 (M+H).

Example 307 Preparation of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-(2-(3-methylbutanamido)ethyl)benzoicacid I-307 Step A. Preparation of3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid

Title compound was prepared according to the procedure used in Example306 by substituting potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate for(4-hydroxyphenyl)boronic acid. MS (ES) 816.0 (M+H).

Step B. Preparation of3-(2-aminoethyl)-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid

To a stirred solution of3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid (0.055 mmol) in THF (0.1 M) was added a solution of 4M HCl indioxane (0.5 mmol) and the reaction allowed to stir for 12 hours beforeremoving the volatiles via rotary evaporation. The residue was thenslurried in 0.5 mL of 1:1 mix of acetonitrile and methanol. The slurrywas filtered and the filtrate was purified by reverse phase preparatoryHPLC (H₂O/CH₃CN gradient from 5 to 95% CH₃CN 0.1% TFA) to yield thetitle compound. MS (ES) 716.1 (M+H).

Step C. Example 307

To a stirred solution of3-(2-aminoethyl)-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid (0.006 mmol) in DCM (0.05M) and TEA (0.015 mmol) was addedisovaleryl chloride (0.017 mmol). The reaction mixture was allowed tostir for 15 hours at room temperature. Upon completion the volatileswere removed via rotary evaporation and the residue was then slurried in0.5 mL of 1:1 mix of acetonitrile and methanol. The slurry was filteredand the filtrate was purified by reverse phase preparatory HPLC(H₂O/CH₃CN gradient from 5 to 95% CH₃CN 0.1% TFA) to yield the titlecompound. MS (ES) 800.1 (M+H).

Example 308 Preparation of5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-4′-((2-(trifluoromethyl)benzyl)oxy)-[1,1′-biphenyl]-3-carboxylicacid I-308

To a stirred solution of5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-4′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid (0.033 mmol) in DCM (0.1 M) and 0.25 mL 50% NaOH (aq) was added1-(bromomethyl)-2-(trifluoromethyl)benzene (0.198 mmol) at roomtemperature. The reaction stirred for 3 days before acidifying to a pHof 2 with 3M HCl (aq) for extraction with ethyl acetate. The aqueousphase was extracted three times, the combined organics were then washedwith brine, dried over magnesium sulfate, filtered and volatiles wereremoved in vacuo. The crude material was then slurried in 0.5 mL of 1:1mix of acetonitrile and methanol. The slurry was filtered and thefiltrate was purified by reverse phase preparatory HPLC (H₂O/CH₃CNgradient from 50% to 95% CH₃CN 0.1% TFA) to yield the title compound. MS(ES) 923.0 (M+H).

Example 309 Preparation ofN-((4-(benzyloxy)phenyl)sulfonyl)-4-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzamideI-309

To a stirred solution of EDC (0.148 mmol), DMAP (0.223 mmol),4-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid (0.074 mmol) in DCM (0.1M) and TEA (0.223 mmol) was added4-(benzyloxy)benzenesulfonamide (0.089 mmol). The reaction mixture wasallowed to stir for 15 hours. Upon completion the volatiles were removedvia rotary evaporation and the remaining material slurried in 1 mL of1:1 mix of acetonitrile and methanol. The slurry was filtered and thefiltrate was purified by reverse phase preparatory HPLC (H₂O/CH₃CNgradient to from 50-95% CH₃CN 0.1% TFA) to yield the title compound as awhite solid. MS (ES) 918.0 (M+H).

Example 310 Preparation of4-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-N-((4-(pyridin-3-ylmethoxy)phenyl)sulfonyl)benzamideI-310

The title compound was prepared according to the procedure used inExample 309 by substituting 4-(pyridin-3-ylmethoxy)benzenesulfonamidefor 4-(benzyloxy)benzenesulfonamide. MS (ES) 919.0 (M+H).

Example 311 Preparation of3-bromo-5-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid I-311

Title compound was prepared according to the procedure used in Example296 by substituting8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 751.1 (M+H).

Example 312 Preparation of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-((2-(trifluoromethyl)phenoxy)methyl)benzoicacid I-312

Title compound was prepared according to the procedure used in Example296 by substituting3-(bromomethyl)-5-((2-(trifluoromethyl)phenoxy)methyl)benzoic acid and8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-onefor methyl 3-bromo-5-(bromomethyl)benzoate and11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one,respectively. MS (ES) 847.2 (M+H).

Example 313 Preparation of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(1H-pyrazol-3-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-313

To a solution of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.043 mmol) in CH₂Cl₂ (1 mL) were added 1H-pyrazol-3-amine(4 μL, 0.086 mmol), EDCI (17 mg, 0.086 mmol, 2 eqv.), DMAP (11 mg, 0.086mmol, 2 eqv.) and the mixture was stirred at room temperature for 16 hat which time LC analysis indicated complete consumption of the startingmaterial. The reaction mixture was extracted in CH₂Cl₂ (3×15 mL), dried(anhyd. Na₂SO₄), evaporated and finally purified by the reverse phaseHPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-90% CH₃CN, 0.1%TFA) to give the title compound (19 mg, 83%) as a colorless solid; MS(ES) 531.1 (M+H); ¹H NMR (400 MHz, DMSO-d⁶) δ 8.26 (d, J=3.1 Hz, 1H),7.79-7.60 (m, 1H), 7.19-7.14 (m, 2H), 6.75 (s, 2H), 6.03 (d, J=3.1 Hz,1H), 4.00 (t, J=6.20 Hz, 2H), 3.80 (s, 3H), 2.27 (s, 6H), 2.20 (s, 3H),2.13 (s, 3H), 2.12-1.97 (m, 4H).

Example 314 Preparation of(1R,2S)-2-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclopentane-1-carboxylicacid I-314

To a solution of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.043 mmol) in DMF (1 mL) were added ethyl(1R,2S)-2-aminocyclopentane-1-carboxylate (43 mg, 0.086 mmol), HBTU (60mg, 0.158 mmol), triethylamine (48 μL, 0.344 mmol), and the mixture wasstirred at room temperature for 24 h at which time LC analysis indicatedcomplete consumption of the starting material. Aqueous lithium hydroxidesolution (2 M, 1 mL) was added to the mixture and stirring was continuedfor additional 24 h. The volatiles were evaporated from the mixture in arotary evaporator followed by acidification with 4M HCl to pH 7. Thereaction mixture was extracted in ethyl acetate (3×15 mL), dried (anhyd.Na₂SO₄), evaporated and finally purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-75% CH₃CN, 0.1% TFA)to give the title compound (23 mg, 91%) as a colorless solid; MS (ES)577.0 (M+H).

Example 315 Preparation of(1s,4s)-4-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclohexane-1-carboxylicacid I-315

The title compound was prepared (67.4 mg, 0.114 mmol, 82%) according toprocedures described in Example 314 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (64 mg, 0.139 mmol), ethyl (1s,4s)-4-aminocyclohexane-1-carboxylate(39 mg, 0.279 mmol), HBTU (60 mg, 0.158 mmol), triethylamine (48 μL,0.344 mmol), and DMF (1 mL); MS (ES) 599.10 (M+H); ¹H NMR (400 MHz,DMSO-d⁶) δ 10.54 (s, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.56 (d, J=7.9 Hz,1H), 7.07 (t, J=7.5 Hz, 1H), 6.93 (d, J=6.9 Hz, 1H), 6.74 (s, 2H), 3.96(t, J=6.4 Hz, 2H), 3.77 (s, 3H), 3.23 (t, J=0.3 Hz, 2H), 2.55-2.47 (m,6H), 2.27 (s, 6H), 2.10 (s, 3H), 2.03 (s, 3H), 1.76-1.63 (m, 2H),1.62-1.41 (m, 4H).

Example 316 Preparation of(1R,2S)-2-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclohexane-1-carboxylicacid I-316

The title compound was prepared (20 mg, 0.034 mmol, 79%) according toprocedures described in Example 314 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.043 mmol), ethyl (1R,2S)-2-aminocyclohexane-1-carboxylate(39 mg, 0.279 mmol), HBTU (60 mg, 0.158 mmol), triethylamine (48 μL,0.344 mmol), and DMF (1 mL); MS (ES) 599.1 (M+H); ¹H NMR (400 MHz,DMSO-d⁶) δ 10.73 (s, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.57 (d, J=7.6 Hz,1H), 7.07 (t, J=7.6 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.76 (s, 2H),4.31-4.15 (m, 1H), 3.98 (t, J=6.4 Hz, 2H), 3.77 (s, 3H), 3.30-3.12 (m,2H), 2.87-2.78 (m, 1H), 2.27 (s, 6H), 2.12 (s, 3H), 2.05 (s, 3H),2.04-1.93 (m, 3H), 1.92-1.83 (m, 1H), 1.72-1.53 (m, 3H), 1.51-1.31 (m,3H).

Example 317 Preparation of(1R,3R)-3-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclohexane-1-carboxylicacid I-317

The title compound was prepared (22 mg, 0.037 mmol, 86%) according toprocedures described in Example 314 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.043 mmol), ethyl (1R,3R)-3-aminocyclohexane-1-carboxylate(38 mg, 0.221 mmol), HBTU (60 mg, 0.158 mmol), triethylamine (48 μL,0.344 mmol), and DMF (1 mL); MS (ES) 599.1 (M+H).

Example 318 Preparation of3-(4-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)piperidin-1-yl)-3-oxopropanoicacid I-318 Step A. Synthesis of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(piperidin-4-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide

To a solution of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.043 mmol) in DMF (1 mL) were added benzyl4-aminopiperidine-1-carboxylate (12 mg, 0.047 mmol), HBTU (60 mg, 0.158mmol), triethylamine (48 μL, 0.344 mmol), and the mixture was stirred atroom temperature for 12 h at which time LC analysis indicated completeconsumption of the starting material. The reaction mixture was extractedin CH₂Cl₂ (3×15 mL), dried (anhyd. Na₂SO₄), evaporated. The crude wastaken in MeOH (1 mL) and was added Pd/C (5 mg, 0.05 mmol, 10 mol %) andthe mixture was hydrogenated with H₂ balloon for 12 h. The reactionmixture was filtered through celite, extracted in CH₂Cl₂ (3×15 mL),dried (anhyd. Na₂SO₄), evaporated and was purified by the reverse phaseHPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-75% CH₃CN, 0.1%TFA) to the title compound (22 mg, 92%) as a colorless solid: MS (ES)548.1 (M+H).

Step B.3-(4-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)piperidin-1-yl)-3-oxopropanoicacid

The title compound was prepared (13.5 mg, 0.021 mmol, 53%) according toprocedures described in Example 314 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(piperidin-4-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide(22 mg, 0.04 mmol), ethyl hydrogen malonate (12 μL, 0.086 mmol), HBTU(60 mg, 0.158 mmol), triethylamine (48 μL, 0.344 mmol), and DMF (1 mL);MS (ES) 634.1 (M+H).

Example 319 Preparation of2-(4-(3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)piperidin-1-yl)-2-oxoaceticacid I-319

To a solution of3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(piperidin-4-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide(24 mg, 0.043 mmol) in CH₂Cl₂ (1 mL) at 0° C. were added triethylamine(24 μL, 0.172 mmol) and the mixture was stirred at that temperature for10 min. Ethyl chlorooxoacetate (6 μL, 0.0473 mmol, 1.1 eqv.) was thenadded to the mixture and the mixture was stirred at room temperature for12 h at which time LC analysis indicated complete consumption of thestarting material. The reaction mixture was extracted in CH₂Cl₂ (3×15mL), dried (anhyd. Na₂SO₄), evaporated. The crude was taken in THF (1mL) and was added with aqueous lithium hydroxide solution (2M, 1 mL).The mixture was stirred at room temperature for 6 h. The volatiles wereevaporated from the mixture in a rotary evaporator followed byacidification with 4M HCl to pH 7. The reaction mixture was extracted inethyl acetate (3×15 mL), dried (anhyd. Na₂SO₄), evaporated and finallypurified purified by the reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 30-70% CH₃CN, 0.1% TFA) to the title compound(24 mg, 89%) as a white solid; MS (ES) 620.1 (M+H); ¹H NMR (400 MHz,DMSO-d⁶) δ 10.44 (s, 1H), 8.17 (d, J=7.2 Hz, 1H), 7.58 (d, J=7.8 Hz,1H), 7.08 (dd, J=7.8 & 7.2 Hz, 1H), 6.98 (d, J=6.8 Hz, 1H), 6.75 (s,2H), 5.75 (s, 1H), 3.96 (t, J=6.4 Hz, 2H), 3.76 (s, 3H), 3.30-3.18 (m,4H), 2.88 (dt, J=10.5 & 1.5 Hz, 1H), 2.27 (s, 6H), 2.09 (s, 3H),2.06-2.03 (m, 2H), 2.02 (s, 3H), 1.99-1.89 (m, 2H), 1.28-1.17 (m, 4H).

Example 320 Preparation of(1R,4R)-4-((3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)cyclohexane-1-carboxylicacid I-320

The title compound was prepared (17 mg, 0.028 mmol, 66%) according toprocedures described in Example 314 using3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.043 mmol), ethyl(1R,4R)-4-(aminomethyl)cyclohexane-1-carboxylate (46 mg, 0.248 mmol),HBTU (60 mg, 0.158 mmol), triethylamine (48 μL, 0.344 mmol), and DMF (1mL); MS (ES) 605.2 (M+H).

Example 321 Preparation of2-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)piperidin-11-yl)-2-oxoaceticacid I-321

The title compound was prepared (9 mg, 0.013 mmol, 31%) according toprocedures described in Example 318 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (22 mg, 0.043 mmol), benzyl 4-aminopiperidine-1-carboxylate (12 mg,0.047 mmol, 1.1 eqv.); MS (ES) 654.0 (M+H).

Example 322 Preparation of(1R,3R)-3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclohexane-1-carboxylicacid I-322

The title compound was prepared (8.4 mg, 0.013 mmol, 58%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (12 mg, 0.023 mmol), ethyl (1S,3S)-3-aminocyclohexane-1-carboxylate(14 mg, 0.079 mmol), HBTU (60 mg, 0.158 mmol), triethylamine (48 μL,0.344 mmol), and DMF (1 mL); MS (ES) 625.0 (M+H).

Example 323 Preparation of2-((1-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)azetidin-3-yl)amino)-2-oxoaceticacid I-323

To a solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.04 mmol) in DMF (1 mL) were added tert-butylazetidin-3-ylcarbamate (9 mg, 0.04 mmol), HBTU (60 mg, 0.158 mmol),triethylamine (48 μL, 0.344 mmol), and the mixture was stirred at roomtemperature for 12 h at which time LC analysis indicated completeconsumption of the starting material. The reaction mixture was extractedin CH₂Cl₂ (3×15 mL), dried (anhyd. Na₂SO₄), evaporated. The crude wastaken in dioxane (1 mL) and was added 6N HCl (1 mL) and the mixture washeated to 50° C. with for 2 h. Aqueous NaHCO₃ solution (3 mL) was addedand the reaction mixture was extracted in CH₂Cl₂ (3×15 mL), dried(anhyd. Na₂SO₄), evaporated. The crude was taken in CH₂Cl₂ (1 mL) andtriethylamine (24 μL, 0.172 mmol) was added to the mixture at 0° C. Themixture was stirred at that temperature for 10 mins. Ethylchlorooxoacetate (6 μL, 0.0473 mmol, 1.1 eqv.) was then added to themixture and the mixture was stirred at room temperature for 12 h atwhich time LC analysis indicated complete consumption of the startingmaterial. The reaction mixture was extracted in CH₂Cl₂ (3×15 mL), dried(anhyd. Na₂SO₄), evaporated. The crude was taken in THF (1 mL) and wasadded with aqueous lithium hydroxide solution (2M, 1 mL). The mixturewas stirred at room temperature for 6 h. The volatiles were evaporatedfrom the mixture in a rotary evaporator followed by acidification with4M HCl to pH 7. The reaction mixture was extracted in ethyl acetate(3×15 mL), dried (anhyd. Na₂SO₄), evaporated and finally purified by thereverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from30-70% CH₃CN, 0.1% TFA) to the title compound (3 mg, 11%) as a colorlesssolid; MS (ES) 626.0 (M+H).

Example 324 Preparation of(1r,4r)-4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)cyclohexane-1-carboxylicacid I-324

The title compound was prepared (8 mg, 0.013 mmol, 69%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (9 mg, 0.018 mmol), ethyl(1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylate (11 mg, 0.057 mmol),HBTU (25 mg, 0.066 mmol), triethylamine (20 μL, 0.144 mmol), and DMF (1mL); MS (ES) 639.1 (M+H).

Example 325 Preparation of(S)-2-(3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)pyrrolidin-1-yl)-2-oxoaceticacid I-325

The title compound was prepared (21 mg, 0.033 mmol, 56%) according toprocedures described in Example 318 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (30 mg, 0.06 mmol), (S)-1-benzylpyrrolidin-3-amine (22 μL, 0.125mmol); MS (ES) 640.0 (M+H).

Example 326 Preparation of(R)-2-(3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)pyrrolidin-1-yl)-2-oxoaceticacid I-326

The title compound was prepared (24 mg, 0,037 mmol, 64%) according toprocedures described in Example 318 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (30 mg, 0.06 mmol), (R)-1-benzylpyrrolidin-3-amine (22 μL, 0.125mmol); MS (ES) 640.0 (M+H).

Example 327 Preparation of(R)-2-(3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)piperidin-1-yl)-2-oxoaceticacid I-327

The title compound was prepared (20 mg, 0.031 mmol, 51%) according toprocedures described in Example 318 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (30 mg, 0.06 mmol), (R)-1-benzylpiperidin-3-amine (23 μL, 0.125mmol); MS (ES) 654.0 (M+H).

Example 328 Preparation of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-(isopentylamino)benzoicacid I-328 Step A. Synthesis of3-amino-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid

To a solution of3-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-nitrobenzoicacid (42 mg, 0.058 mmol) in MeOH (2 mL) was added Pd/C (5.8 mg, 0.058mmol) and the mixture was hydrogenated with H₂ balloon for 12 h. Thereaction mixture was filtered through celite, extracted in CH₂Cl₂ (3×15mL), dried (anhyd. Na₂SO₄), evaporated and was purified by the reversephase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-70% CH₃CN,0.1% TFA) to give the title compound (36 mg, 91%) as a white solid: MS(ES) 688.1 (M+H).

Step B. Example 328

To a methanolic solution of3-amino-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid (10 mg, 0.015 mmol) in MeOH (0.5 mL) was added isovaleraldehyde (10μL, 0.086 mmol) and the reaction mixture was stirred at room temperaturefor 30 mins. Sodium borohydride (2 mg, 0.043, 1.5 eqv.) was added to themixture and stirring was continued for additional 4 h. The reactionmixture was filtered through celite, extracted in CH₂Cl₂ (3×5 mL), dried(anhyd. Na₂SO₄), evaporated and was purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-70% CH₃CN, 0.1% TFA)to give the title compound (8 mg, 70%) as a white solid: MS (ES) 758.1(M+H).

Example 329 Preparation of3-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-5-(3-methyl-N-(3-methylbutanoyl)butanamido)benzoicacid I-329

To a solution of3-amino-5-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)benzoicacid (10 mg, 0.015 mmol) in CH₂Cl₂ (1 mL) were added DMAP (7 mg, 0.06mmol) and isovaleryl chloride (20 μL, 0.136 mmol), and the mixture wasstirred at room temperature for 3 h at which time LC analysis indicatedcomplete consumption of the starting material. The reaction mixture wasextracted in CH₂Cl₂ (3×15 mL), dried (anhyd. Na₂SO₄), evaporated andfinally purified by the reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 30-70% CH₃CN, 0.1% TFA) to give the titlecompound (7.2 mg, 56%) as a white solid; MS (ES) 856.1 (M+H).

Example 330 Preparation of(1R,3S)-3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclopentane-1-carboxylicacid I-330

The title compound was prepared (18.5 mg, 0.03 mmol, 44%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (35 mg, 0.018 mmol), ethyl(1R,3S)-3-aminocyclopentane-1-carboxylate (11 mg, 0.069 mmol), HBTU (25mg, 0.067 mmol), triethylamine (20 μL, 0.144 mmol), and DMF (1 mL); MS(ES) 611.1 (M+H).

Example 331 Preparation of(1R,3S)-3-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclohexane-1-carboxylicacid I-331

The title compound was prepared (42.5 mg, 0.068 mmol, 68%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (50 mg, 0.1 mmol), ethyl (1R,3S)-3-aminocyclohexane-1-carboxylate(19 mg, 0.1 mmol), HBTU (140 mg, 0.37 mmol), triethylamine (112 μL, 0.8mmol), and DMF (1 mL); MS (ES) 625.0 (M+H).

Example 332 Preparation of(1s,4s)-4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclohexane-1-carboxylicacid I-332

The title compound was prepared (11 mg, 0.017 mmol, 44%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.04 mmol), ethyl (1s,4s)-4-aminocyclohexane-1-carboxylate(11 mg, 0.06 mmol), HBTU (56 mg, 0.148 mmol), triethylamine (45 μL, 0.32mmol), and DMF (1 mL); MS (ES) 625.0 (M+H).

Example 333 Preparation of(1R,2S)-2-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclohexane-1-carboxylicacid I-333

The title compound was prepared. (13 mg, 0.021 mmol, 52%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.04 mmol), ethyl (1R,2S)-2-aminocyclohexane-1-carboxylate(11 mg, 0.06 mmol), HBTU (56 mg, 0.148 mmol), triethylamine (45 μL, 0.32mmol), and DMF (1 mL); MS (ES) 625.0 (M+H).

Example 334 Preparation of(1R,2S)-2-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)cyclopentane-1-carboxylicacid I-334

The title compound was prepared (14.3 mg, 0.023 mmol, 59%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (20 mg, 0.04 mmol), ethyl (1R,2S)-2-aminocyclopentane-1-carboxylate(8 mg, 0.06 mmol), HBTU (56 mg, 0.148 mmol), triethylamine (45 μL, 0.32mmol), and DMF (1 mL); MS (ES) 611.1 (M+H).

Example 335 Preparation of4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoicacid I-335

The title compound was prepared (156 mg, 0.226 mmol, 76%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (150 mg, 0.299 mmol), ethyl 4-(piperazin-1-yl)benzoate (71 mg,0.299 mmol), HBTU (420 mg, 1.106 mmol); triethylamine (334 μL, 2.392mmol), and DMF (20 mL); MS (ES) 688.0 (M+H); ¹H NMR (400 MHz, DMSO-d⁶) δ10.93 (s, 1H), 7.78 (d, J=8.9 Hz, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.19 (d,J=8.4 Hz, 1H), 6.93 (d, J=8.9 Hz, 2H), 6.71 (s, 2H), 3.95 (t, J=6.7 Hz,2H), 3.75 (s, 3H), 3.35-3.24 (m, 4H), 2.86 (t, J=7.3 Hz, 2H), 2.29-2.25(m, 2H), 2.21 (s, 6H), 2.05-2.02 (m, 2H), 2.02 (s, 3H), 1.98-1.97 (m,1H), 1.96 (s, 3H), 1.95-1.93 (m, 1H).

Example 336 Preparation of1-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)pyrrolidine-3-carboxylicacid I-336

The title compound was prepared (26 mg, 0.043 mmol, 55%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.079 mmol), methyl pyrrolidine-3-carboxylate (10.2 mg,0.079 mmol), HBTU (111 mg, 0.292 mmol), triethylamine (88 μL, 0.632mmol), and DMF (1 mL); MS (ES) 597.0 (M+H).

Example 337 Preparation of(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)-L-prolineI-337

The title compound was prepared (18 mg, 0.03 mmol, 38%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (40 mg, 0.079 mmol), methyl L-prolinate (13 mg, 0.079 mmol), HBTU(111 mg, 0.292 mmol), triethylamine (88 μL, 0.632 mmol), and DMF (1 mL);MS (ES) 597.0 (M+H).

Example 338 Preparation of4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(pyridin-3-ylmethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoic acidI-338

To a solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (25 mg, 0.05 mmol) in DMF (1 mL) at rt were added methyl4-(piperazin-1-yl)benzoate (11 mg, 0.05 mmol), HBTU (70 mg, 0.185 mmol),triethylamine (56 μL, 0.4 mmol) and the mixture was stirred at rt for 10h at which time LC showed complete disappearance of starting carboxylicacid. Water (5 mL) was added to the mixture and it was extracted inCH₂Cl₂ (3×5 mL). The organic layer was dried (anhyd. Na₂SO₄) and wasevaporated. The crude was taken in DMF (1 mL) and NaH (6 mg, 0.15 mmol)at room temperature and the mixture was stirred for 30 min at ambienttemperature. A solution of 3-(bromomethyl)pyridine hydrobromide (15 mg,0.06 mmol) in DMF (1 mL) was added drop wise to the reaction mixture atroom temperature and stirring was continued for additional 2 h. Themixture was diluted with water (4 mL) and extracted in CH₂Cl₂ (3×5 mL).The organic layer was dried (anhyd. Na₂SO₄) and was evaporated. To asolution of crude ester in THF (2 mL) at room temperature was added 2MLiOH (1 mL) the mixture was stirred at the ambient temperature for 10 h.The reaction mixture was evaporated, acidified to pH 7 with 4M HCl,extracted in EtOAc. The organic layer was dried, evaporated and finallypurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient from 30-70% CH₃CN, 0.1% TFA) to give the title compound (37 mg,95%) as a white solid; MS (ES) 779.1 (M+H).

Example 339 Preparation of4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoicacid I-339

The title compound was prepared (17 mg, 0.024 mmol, 83%) according toprocedures described in Example 338 using methyl4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoate(20 mg, 0.029 mmol), methyl iodide (8 μL, 0.116 mmol), NaH (4.6 mg,0.116 mmol) and DMF (1 mL); MS (ES) 702.1 (M+H).

Example 340 Preparation of4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(pyridin-4-ylmethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoicacid I-340

The title compound was prepared (37 mg, 0.048 mmol, 95%) according toprocedures described in Example 338 using methyl4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoate(20 mg, 0.029 mmol), 4-(bromomethyl)pyridine hydrobromide (15 mg, 0.06mmol), NaH (4.6 mg, 0.116 mmol) and DMF (1 mL); MS (ES) 779.1 (M+H).

Example 341 Preparation of4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(pyridin-2-ylmethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoicacid I-341

The title compound was prepared (35 mg, 0.046 mmol, 91%) according toprocedures described in Example 338 using methyl4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoate(20 mg, 0.029 mmol), 2-(bromomethyl)pyridine hydrobromide (15 mg, 0.06mmol), NaH (4.6 mg, 0.116 mmol) and DMF (1 mL); MS (ES) 779.1 (M+H).

Example 342 Preparation of4-(4-(1-benzyl-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1-indole-2-carbonyl)piperazin-1-yl)benzoicacid I-342

The title compound was prepared (35 mg, 0.045 mmol, 90%) according toprocedures described in Example 338 using methyl4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoate(20 mg, 0.029 mmol), benzyl bromide (8 μL, 0.06 mmol), NaH (4.6 mg,0.116 mmol) and DMF (1 mL); MS (ES) 778.0 (M+H).

Example 343 Preparation of4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoicacid I-343

The title compound was prepared (29 mg, 0.036 mmol, 72%) according toprocedures described in Example 338 using methyl4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)benzoate(20 mg, 0.029 mmol), 4-(2-bromoethyl)morpholine (12 mg, 0.06 mmol), NaH(4.6 mg, 0.116 mmol) and DMF (1 mL); MS (ES) 802.0 (M+H).

Example 344 Preparation of6-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)piperazin-1-yl)nicotinicacid I-344 Step A. Synthesis of methyl 6-(piperazin-1-yl)nicotinate

To a solution of methyl 6-chloronicotinate (343 mg, 2 mmol) in MeOH (6mL) at room temperature was added piperazine (860 mg, 10 mmol) and themixture was heated to 60° C. for 6 h. The mixture was evaporated and thecrude was purified by the reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 30-70% CH₃CN, 0.1% TFA) to give the titlecompound (422 mg, 95%) as a colorless solid; MS (ES) 222.20 (M+H).

Step B. Example 344

The title compound was prepared (31 mg, 0.036 mmol, 90%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (25 mg, 0.05 mmol), methyl 6-(piperazin-1-yl)nicotinate (13 mg,0.079 mmol), HBTU (70 mg, 0.185 mmol), triethylamine (56 μL, 0.4 mmol),and DMF (1 mL); MS (ES) 689.1 (M+H); ¹H NMR (400 MHz, DMSO-d⁶) δ 10.92(s, 1H), 8.63 (d, J=2.3 Hz, 1H), 7.96 (dd, J=9.0 & 2.3 Hz, 1H), 7.58 (d,J=8.6 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 6.71 (s,2H), 3.95 (t, J=6.1 Hz, 2H), 3.73 (s, 3H), 3.68-3.56 (m, 6H), 2.86 (t,J=7.3 Hz, 2H), 2.62-2.51 (m, 2H), 2.20 (s, 6H), 2.06-2.03 (m, 1H), 2.01(s, 3H), 2.00-1.98 (m, 1H), 1.95 (s, 3H).

Example 345 Preparation of7-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indole-3-carboxylicacid I-345 Step A. Synthesis of8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one

To a solution of ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(102 mg, 0.193 mmol) in DMF (1 mL) at room temperature was addedtert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (55 mg, 0.23mmol) and the mixture was stirred at room temperature for 10 min. NaH (6mg, 0.249 mmol, 1.3 eqiv.) was added to the mixture and stirring wascontinued to additional 2 h. The mixture was diluted with NH₄Cl (4 mL)and extracted in DCM (3×5 mL). The organic layer was dried (anhyd.Na₂SO₄) and was evaporated. To a solution of crude in dioxane (2 mL) wasadded 4M HCl and the mixture was stirred at 50° C. for overnight.Saturated aqueous NaHCO₃(4 mL) solution was added to the mixture and itwas extracted in DCM (3×5 mL). The organic layer was evaporated and thecrude was taken in MeOH (2 mL) followed by potassium carbonate (111 mg,0.806 mmol) and the mixture was heated at 50° C. for overnight. Themixture was acidified to pH 7 with 4M HCl, extracted in DCM (3×5 mL).The organic layer was dried, evaporated and finally purified in Gilson(30-70% acetonitrile in water) to the title compound (96 mg, 93%) as acolorless solid; MS (ES) 539.1 (M+H).

Step B Preparation of methyl 7-bromo-1-methyl-1H-indole-3-carboxylate

To a solution of methyl 7-bromo-1H-indole-3-carboxylate (330 mg, 1.29mmol) in DMF (2 mL) was added dimethyl carbonate (1.086 mL, 12.9 mmol)followed by DABCO (15 mg, 0.13 mmol, 10 mol %) and the mixture washeated at 100° C. for 10 h. The mixture was diluted with NH₄Cl (4 mL)and extracted in DCM (3×5 mL). The organic layer was dried (anhyd.Na₂SO₄), evaporated and finally purified by the reverse phase HPLC(Phenomenex Gemini C18, H₂O/CH₃CN gradient from 30-70% CH₃CN, 0.1% TFA)to give the title compound (259 mg, 75%) as a white solid; MS (ES) 268.0(M+2).

Step C. Example 345

To a solution of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(54 mg, 0.1 mmol) in dioxane (2 mL) was added methyl7-bromo-1-methyl-1H-indole-3-carboxylate (32 mg, 0.12 mmol), Xantphos(3.5 mg, 0.006 mmol, 6 mol %), Pd₂(dba)₃ (2 mg, 0.002 mmol, 2 mol %),cesium carbonate (49 mg, 0.15 mmol) and the mixture was purged with Arfor 30 min. The mixture was heated at 110° C. for 16 h. The mixture wasdiluted with NH₄Cl (4 mL) and extracted in DCM (3×5 mL). The organiclayer was dried (anhyd. Na₂SO₄), evaporated. To a solution of crudeester in THF (2 mL) at room temperature was added 2M LiOH (1 mL) themixture was stirred at the ambient temperature for 10 h. The reactionmixture was evaporated, acidified to pH 7 with 4M HCl, extracted inEtOAc. The organic layer was dried, evaporated and purified by thereverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from30-70% CH₃CN, 0.1% TFA) to give the title compound (58 mg, 81%) as awhite solid; MS (ES) 712.0 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (d,J=7.9 Hz, 1H), 8.04 (s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.27 (t, J=8.5 Hz,1H), 7.22 (t, J=7.7 Hz, 1H), 7.13 (dd, J=7.9 & 7.7 Hz, 1H), 6.74 (s,2H), 4.25-3.90 (m, 7H), 3.82 (s, 3H), 3.79 (s, 3H), 3.21-3.08 (m, 1H),3.07-2.90 (m, 1H), 2.26 (s, 6H), 2.18-2.08 (m, 1H), 2.06 (s, 3H), 2.00(s, 3H), 1.97-1.94 (m, 1H), 1.93-1.86 (m, 1H).

Example 346 Preparation of5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-2-oxothiazolidine-4-carboxylicacid I-346

The title compound was prepared (52 mg, 0.076 mmol, 76%) according toprocedures described in Example 345 Step C using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(54 mg, 0.1 mmol), ethyl 5-bromothiazole-4-carboxylate (28 mg, 0.12mmol), Xantphos (3.5 mg, 0.006 mmol, 6 mol %), Pd₂(dba)₃ (2 mg, 0.002mmol, 2 mol %), cesium carbonate (49 mg, 0.15 mmol) and dioxane (2 mL);MS (ES) 684.1 (M+H).

Example 347 Preparation of5-((8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)-2-methylfuran-3-carboxylicacid I-347

To a solution of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (100 mg, 0.2 mmol) in DMF (2 mL) were added methyl5-(aminomethyl)-2-methylfuran-3-carboxylate (41 mg, 0.2 mmol), HBTU (76mg, 0.2 mmol), triethylamine (84 μL, 0.3 mmol), and the mixture wasstirred at room temperature for 10 h at which time LC analysis indicatedcomplete consumption of the starting material. Water (5 mL) was added tothe mixture and it was extracted in CH₂Cl₂ (3×5 mL). The organic layerwas dried (anhyd. Na₂SO₄) and was evaporated. To the solution crude inDMF (3 mL) were added 1,3-dibromopropane (31 μL, 0.3 mmol), Cs₂CO₃ (130mg, 0.4 mmol) and the mixture was stirred at 40° C. for 6 h. The mixturewas filtered, diluted with water (5 mL) and was extracted in CH₂Cl₂ (3×5mL). The organic layer was dried (anhyd. Na₂SO₄) and was evaporated. Toa solution of crude ester in THF (2 mL) at room temperature was added 2MLiOH (1 mL) the mixture was stirred at the ambient temperature for 10 h.The reaction mixture was evaporated, acidified to PH 7 with 4M HCl,extracted in EtOAc. The organic layer was dried, evaporated and finallypurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CNgradient from 30-70% CH₃CN, 0.1% TFA) to give the title compound (116mg, 86%) as a colorless solid; MS (ES) 677.2 (M+H); ¹H NMR (400 MHz,DMSO-d⁶) δ 7.66 (d, J=8.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.71 (s, 2H),6.53 (s, 1H), 4.65-4.49 (m, 2H), 3.92 (t, J=6.2 Hz, 2H), 3.75 (s, 3H),3.73-3.65 (m, 2H), 3.21 (t, J=5.9 Hz, 2H), 3.02 (t, J=7.1 Hz, 2H), 2.46(s, 3H), 2.26 (s, 6H), 2.05 (q, J=6.8 Hz, 2H), 1.99 (s, 1H), 1.95 (s,3H), 1.91 (s, 1H), 1.86 (s, 3H).

Example 348 Preparation of2-(4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indol-1-yl)aceticacid I-348 Step A. Preparation of tert-butyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-1-carboxylate

The title compound was prepared (71 mg, 0.094 mmol, 94%) according toprocedures described in Example 345 Step C using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(54 mg, 0.1 mmol), tert-butyl 4-bromo-1H-indole-1-carboxylate (36 mg,0.12 mmol), Xantphos (3.5 mg, 0.006 mmol, 6 mol %), Pd₂(dba)₃ (2 mg,0.002 mmol, 2 mol %), cesium carbonate (49 mg, 0.15 mmol) and dioxane (2mL); MS (ES) 754.3 (M+H).

Step B. Synthesis of2-(4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indol-1-yl)aceticacid

To a solution of tert-butyl4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1H-indole-1-carboxylate(71 mg, 0.094 mmol) in DCM (2 mL) TFA (2 mL) was added and the mixturewas stirred at room temperature for 6 h. Saturated aqueous NaHCO₃(8 mL)was added to the mixture and it was extracted in DCM (3×5 mL). Theorganic layer was dried (anhyd. Na₂SO₄), evaporated. To a solution ofcrude in DMF (1 mL) was added NaH (5 mg, 0.12 mmol, 1.2 eqv.) and themixture was stirred at room temperature for 10 mins. Ethyl bromoacetate(14 μL, 0.12 mmol, 1.2 eqv.) was added to the mixture and it was stirredat ambient temperature for 2 h. The mixture was diluted with water (5mL) and was extracted in CH₂Cl₂ (3×5 mL). The organic layer was dried(anhyd. Na₂SO₄) and was evaporated. To a solution of crude ester in THF(2 mL) at room temperature was added 2M LiOH (1 mL) the mixture wasstirred at the ambient temperature for 10 h. The reaction mixture wasevaporated, acidified to pH 7 with 4M HCl, extracted in ETOAc. Theorganic layer was dried, evaporated and finally purified in Gilson(30-70% acetonitrile in water) to the title compound (48 mg, 72%) as abrown solid; MS (ES) 712.2 (M+H); ¹H NMR (400 MHz, DMSO-d⁶) δ 7.72 (d,J=8.6 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.34 (d, J=3.2 Hz, 1H), 7.27 (d,J=8.6 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.73 (s,2H), 6.29 (d, J=3.2 Hz, 1H), 4.11 (t, J=6.5 Hz, 2H), 3.97 (t, J=6.5 Hz,2H), 3.78 (s, 3H), 3.72-3.61 (m, 4H), 3.05 (t, J=7.4 Hz, 2H), 2.25 (s,6H), 2.14-2.05 (m, 2H), 2.03 (s, 3H), 1.93 (s, 3H), 1.81-1.67 (m, 2H).

Example 349 Preparation of2-chloro-6-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)isonicotinicacid I-349

To a solution of8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(54 mg, 0.1 mmol) in DMF (2 mL) was added NaH (5 mg, 0.12 mmol) and themixture was stirred at room temperature for 10 min. Methyl2-(bromomethyl)-6-chloroisonicotinate (32 mg, 0.12 mmol) was added tothe mixture followed by TBAI (37 mg, 0.1 mmol) and stirring wascontinued for additional 2 h. The mixture was diluted with water (5 mL)and was extracted in CH₂Cl₂ (3×5 mL). The organic layer was dried(anhyd. Na₂SO₄) and was evaporated. To a solution of crude ester in THF(1 mL) at room temperature was added 2M LiOH (1 mL) the mixture wasstirred at the ambient temperature for 5 h. The reaction mixture wasevaporated, acidified to pH 7 with 4M HCl, extracted in EtOAc. Theorganic layer was dried, evaporated and finally purified in Gilson(30-70% acetonitrile in water) to the title compound (62 mg, 87%) as awhite solid; MS (ES) 708.1 (M+H).

Example 350 Preparation of5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)thiazole-4-carboxylicacid I-350

The title compound was prepared (55 mg, 0.082 mmol, 83%) according toprocedures described in Example 345 Step C using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(54 mg, 0.1 mmol), ethyl 5-bromothiazole-4-carboxylate (28 mg, 0.12mmol), Xantphos (3.5 mg, 0.006 mmol, 6 mol %), Pd₂(dba)₃ (2 mg, 0.002mmol, 2 mol %), cesium carbonate (49 mg, 0.15 mmol) and dioxane (2 mL);MS (ES) 666.1 (M+H).

Example 351 Preparation of5-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-naphthoicacid I-351

The title compound was prepared (62 mg, 0.087 mmol, 87%) according toprocedures described in Example 345 Step C using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(54 mg, 0.1 mmol), methyl 5-bromo-1-naphthoate (32 mg, 0.12 mmol),Xantphos (3.5 mg, 0.006 mmol, 6 mol %), Pd₂(dba)₃ (2 mg, 0.002 mmol, 2mol %), cesium carbonate (49 mg, 0.15 mmol) and dioxane (2 mL); MS (ES)709.2 (M+H); ¹H NMR (400 MHz, DMSO-d⁶) δ 8.86 (d, J=8.5 Hz, 1H), 8.17(d, J=7.1 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.68(dd, J=7.7 & 7.5 Hz, 1H), 7.62-7.51 (m, 2H), 7.28 (d, J=8.6 Hz, 1H),6.73 (s, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.81-3.76 (m, 4H), 3.74 (s, 3H),3.59-3.45 (m, 1H), 3.14-2.94 (m, 2H), 2.23 (s, 6H), 2.13-2.07 (m, 2H),2.05 (s, 3H), 1.93 (s, 3H), 1.83-1.63 (m, 1H).

Example 352 Preparation of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-cyanophenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-352

In a 20-mL scintillation vial equipped with a stir bar,6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid(45 mg, 0.090 mmol), EDC (35 mg, 0.29 mmol), and DMAP (25 mg, 0.16 mmol)were charged and dissolved in DCM (3 mL). The reaction was allowed tostir for 10 min at ambient temperature, followed by addition of3-aminobenzonitrile (20 mg, 0.157 mmol) in 1 mL of DCM. The reaction wasallowed to stir for 6 h at ambient temperature, after which time thereaction was determined to be complete by LCMS. The reaction mixture wasdiluted into DCM/H₂O (1:1, 20 mL). The organic layer was separated, andthe aqueous layer was extracted with DCM (2×10 mL). The combined organicextracts were dried with a phase separator and concentrated in vacuo.The crude material was purified by silca gel flash column chromatography(ISCO Hexanes/EtOAc 0-100% gradient) to afford 24 mg (0.040 mmol) of thetitle compound. MS (ES) 600.0 (M+H).

Example 353 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzonitrileI-353

In a 20-mL scintillation vial equipped with a stir bar,6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-cyanophenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide(24 mg, 0.40 mmol) was charged and dissolved in DMF (2 mL). Cesiumcarbonate (50 mg, 0.154 mmol) was added, followed by addition of1,3-dibromopropane (30 mg, 0.149 mmol). The reaction mixture was stirredfor 4 h at 60° C., after which time the reaction was determined to becomplete by LCMS. The reaction mixture was cooled to ambient temperatureand diluted into DCM/H₂O (1:1, 20 mL). The organic layer was separated,and the aqueous layer was extracted with DCM (2×10 mL). The combinedorganic extracts were dried over a phase separator, and concentrated invacuo. The crude material was dissolved in DMSO (1 mL) and purified bythe reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN 30-95% 0.1%TFA) to give the title compound (16 mg, 0.025 mmol) as a colorless oil.MS (ES) 640.0 (M+H).

Example 354 Preparation of2-(3-(2H-tetrazol-5-yl)phenyl)-8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-354

In a 2-dram vial equipped with a stir bar,3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzonitrile(25 mg, 0.039 mmol) was charged and dissolved in DMF (3 mL). Sodiumazide (15 mg, 0.231 mmol) and ammonium chloride (15 mg, 0.28 mmol) wereadded, and the reaction was allowed to stir at 120° C. for 36 h afterwhich time LCMS confirmed presence of desired product and unreactedstarting material. The reaction was allowed to cool to ambienttemperature, diluted into DCM/H₂O (1:1, 20 mL), and the organic layerwas separated. The aqueous layer was extracted with DCM (2×10 mL), andthe combined organic layers were dried with a phase separator andconcentrated in vacuo. The crude product was dissolved in DMSO (1 mL)and purified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN30-95% 0.1% TFA) to afford 7 mg (0.010 mmol) of the title compound as awhite solid. MS (ES) 683.1 (M+H); ¹H NMR (500 MHz in CDCl₃): δ 8.00 (s,1H), 7.67 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.30 (d, J=8.0 Hz, 1H),7.21-7.18 (m, 2H), 6.52 (s, 2H), 4.20-4.14 (m, 2H), 3.95-3.90 (m, 3H),3.73-3.67 (m, 2H), 3.50 (s, 3H), 3.23 (t, J=6.0 Hz, 2H), 2.24-2.21 (m,2H), 2.19 (s, 6H), 2.12 (s, 3H), 2.10 (3H), 1.94-1.86 (m, 2H).

Example 355 Preparation of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(4-cyanophenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamideI-355

The title compound was prepared according to procedures described inExamples 352 using 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acidand substituting 3-aminobenzonitrile with 4-aminobenzonitrile. MS (ES)683.1 (M+H). MS (ES) 600.0 (M+H).

Example 356 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzonitrileI-356

I The title compound was prepared according to procedures described inExamples 353 substituting6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(3-cyanophenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamidewith6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(4-cyanophenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamide.MS (ES) 640.0 (M+H).

Example 357 Preparation of2-(4-(2H-tetrazol-5-yl)phenyl)-8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-oneI-357

The title compound was prepared (8 mg, 0.012 mmol) as a white solidaccording to procedures described in Examples 354 substituting3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzonitrilewith4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzonitrile(20 mg, 0.157 mmol). MS (ES) 683.1 (M+H).

Example 358 Preparation of2-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)thiazole-5-carboxylicacid I-358

In a 2-dram vial equipped with a stir bar,8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(30 mg, 0.056 mmol), methyl 2-bromothiazole-5-carboxylate (25 mg, 0.113mmol), Pd₂(dba)₃ (5 mg, 0.005 mmol), Xantphos (7 mg, 0.012 mmol), andcesium carbonate (40 mg, 0.123 mmol) were massed. The vial was purgedwith argon, and then 1,4-dioxane (1 mL) was added. The reaction washeated to 110° C. for 16 h, after which time the reaction was determinedto be complete by LCMS. The reaction mixture was cooled to ambienttemperature and diluted into DCM/H₂O (1:1, 20 mL). The organic layer wasseparated, and the aqueous layer was extracted with DCM (2×10 mL). Thecombined organic extracts were dried with a phase separator and thenconcentrated in vacuo. The crude ester was dissolved in DMSO (1 mL) andpurified by the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN30-95% 0.1% TFA). The fractions containing product were concentrated,and resultant residue was dissolved in THF/MeOH/H₂O (2:1:1, 3 mL).Lithium hydroxide (10 mg, 0.417 mmol) was added, and the reaction washeated to 40° C. for 3 h, after which time the reaction was determinedto be complete by LCMS. The reaction was cooled to ambient temperatureand concentrated in vacuo. The crude residue was dissolved in DMSO (1mL) and purified by reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN30-95% 0.1% TFA) to afford 1.3 mg (0.0019 mmol) of the title compound asa colorless oil. MS (ES) 666.0 (M+H).

Example 359 Preparation of2-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)thiazole-4-carboxylicacid I-359

The title compound was prepared (2.3 mg, 0.0035 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(30 mg, 0.056 mmol, 1.00 eq) and substituting methyl2-bromothiazole-5-carboxylate with methyl 2-bromothiazole-4-carboxylate(25 mg, 0.113 mmol). MS (ES) 666.1 (M+H).

Example 360 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)thiazole-2-carboxylicacid I-360

The title compound was prepared (11.5 mg, 0.017 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(30 mg, 0.056 mmol) and substituting methyl2-bromothiazole-5-carboxylate with methyl 4-bromothiazole-2-carboxylate(25 mg, 0.113 mmol). MS (ES) 666.1 (M+H); ¹H NMR: (500 MHz in DMSO-d6) δ8.02 (s, 1H), 7.76 (d, J=0.8.5 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 6.57 (s,2H), 4.10-3.95 (m, 2H), 3.80-3.76 (m, 7H), 3.17 (J=6.5 Hz, 2H), 2.12 (s,6H), 2.08 (t, J=6.5 Hz, 2H), 1.98 (s, 3H), 1.89 (s, 3H), 1.85-1.78 (m,2H).

Example 361 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-N-(cyclopropylsulfonyl)benzamideI-361 Step A. Preparation of 4-bromo-N-(cyclopropylsulfonyl)benzamide

In a scintillation vial, 4-bromobenzoic acid (75 mg, 0.373 mmol) wasdissolved in DCM (3 mL). EDC hydrochloride (100 mg, 0.523 mmol), andDMAP (30 mg, 0.245 mmol) were added and the reaction was allowed to stirfor 5 min. Cyclopropanesulfonamide (100 mg, 0.826 mmol) was added, andthe reaction was allowed to stir at rt for 16 h, after which time thereaction was determined to be complete by LCMS. The reaction was dilutedinto DCM/H₂O (30 mL, 1:1). The organic layer was separated, and theaqueous layer was extracted with DCM (2×20 mL). The combined organicextracts were dried over MgSO₄, filtered, and then concentrated invacuo. The crude material was purified by flash column chromatography(ISCO, Hex/EtOAc 0-100% gradient) to afford the title compound in 96 mg(0.316 mmol, 85% yield) as a white solid. MS (ES) 338.2 (M+H).

Step B. Example 361

The title compound was prepared (6 mg, 0.0079 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(35 mg, 0.065 mmol) and substituting methyl2-bromothiazole-5-carboxylate with4-bromo-N-(cyclopropylsulfonyl)benzamide (30 mg, 0.099 mmol). MS (ES)762.2 (M+H).

Example 362 Preparation of7-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-5-carboxylicacid I-362

The title compound was prepared (6.3 mg, 0.0088 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(35 mg, 0.065 mmol) and substituting methyl2-bromothiazole-5-carboxylate with methyl7-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-5-carboxylate (25 mg, 0.094mmol). MS (ES) 714.3 (M+H).

Example 363 Preparation of7-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzo[d][1,3]dioxole-5-carboxylicacid I-363

The title compound was prepared (4.1 mg, 0.00058 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(35 mg, 0.065 mmol) and substituting methyl2-bromothiazole-5-carboxylate with methyl7-bromobenzo[d][1,3]dioxole-5-carboxylate (25 mg, 0.097 mmol). MS (ES)703.2 (M+H).

Example 364 Preparation of8-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylicacid I-364

The title compound was prepared (2 mg, 0.0028 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(30 mg, 0.056 mmol) and substituting methyl2-bromothiazole-5-carboxylate with methyl8-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (20 mg, 0.073mmol). MS (ES) 717.3 (M+H); ¹H NMR (500 MHz in DMSO-d6) δ 7.70 (d, J=8.5Hz, 1H), 7.40 (dd, J=15, 2.0 Hz, 2H), 7.25 (d, J=8.5 Hz, 1H), 6.74 (s,2H), 4.30 (q, J=3.6 Hz, 4H), 4.08-4.04 (m, 2H), 3.97 (t, J=6.0 Hz, 2H)3.78 (s, 3H), 3.52 (t, J=5.8, 2H), 3.02 (t, J=7.2 Hz, 2H), 2.26 (s, 6H),2.10-2.04 (m, 4H), 2.01 (s, 3H), 1.90 (s, 3H), 1.73-1.71 (m, 2H).

Example 365 Preparation of4-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-benzo[d]imidazole-6-carboxylicacid I-365

The title compound was prepared (2 mg, 0.0028 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(25 mg, 0.046 mmol) and substituting methyl2-bromothiazole-5-carboxylate with methyl4-bromo-1-methyl-1H-benzo[d]imidazole-6-carboxylate (20 mg, 0.075 mmol).MS (ES) 713 (M+H).

Example 366 Preparation of6-(8-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-2-methyl-2H-indazole-4-carboxylicacid I-366 Step A. Preparation of methyl6-bromo-1-methyl-1H-indazole-4-carboxylate and methyl6-bromo-2-methyl-2H-indazole-4-carboxylate

In a 20-mL scintillation vial equipped with a stir bar, methyl6-bromo-1H-indazole-4-carboxylate (100 mg, 0.392 mmol) was dissolved inDMF (5 mL). Sodium hydride (30 mg, 0.75 mmol) was added, and thereaction was allowed to stir at ambient temperature for 1 h. Methyliodide (100 mg, 0.704 mmol) was added, and the reaction was allowed tostir for 2 h, after which time the reaction as determined to be completeby LCMS. The reaction was cooled to 0° C. and quenched with MeOH (0.1mL). The reaction was then diluted into DCM/H₂O (1:1, 20 mL), and theorganic layer was separated. The aqueous layer was extracted with DCM(2×20 mL), and the combined organic layers were dried over a phaseseparator and concentrated in vacuo. The crude residue was dissolved inDMSO (2 mL) and purified by reverse phase HPLC (Phenomenex Gemini C18,H₂O/CH₃CN 30-95% 0.1% TFA) to give methyl6-bromo-1-methyl-1H-indazole-4-carboxylate (A, 32 mg, 0.12 mmol, LCMS:RT=1.418 min, MS (ES) 269.1 (M+H), structure determined by 2D NMR) andmethyl 6-bromo-2-methyl-2H-indazole-4-carboxylate (B, 15 mg, 0.056mmol), LCMS: RT=1.341, MS (ES) 269.1 (M+H), structure determined by 2DNMR).

Step B. Example 366

The title compound was prepared (3 mg, 0.0042 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(25 mg, 0.046 mmol) and substituting methyl2-bromothiazole-5-carboxylate with methyl6-bromo-2-methyl-2H-indazole-4-carboxylate (15 mg, 0.056 mmol). MS (ES)713.2 (M+H); ¹H NMR (500 MHz in DMSO-d6) δ 8.60 (s, 1H), 7.80 (s, 1H),7.74 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.72 (s,2H), 4.22 (s, 3H), 4.06-4.02 (m, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.77 (s,3H), 3.63-3.61 (m, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.21 (s, 6H), 2.08 (t,J=6.5 Hz, 2H), 2.01 (s, 3H), 1.90 (s, 3H), 1.79-1.74 (m, 2H).

Example 367 Preparation of6-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indazole-4-carboxylicacid I-367

The title compound was prepared (4.2 mg, 0.0059 mmol) according toprocedures described in Example 358 using8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one(25 mg, 0.046 mmol) and substituting methyl2-bromothiazole-5-carboxylate with methyl6-bromo-1-methyl-1H-indazole-4-carboxylate (15 mg, 0.056 mmol). MS (ES)713.2 (M+H); ¹H NMR (500 MHz in DMSO-d6) δ 8.32 (s, 1H), 7.97 (s, 1H),7.79 (s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.72 (s,2H), 4.07-4.05 (m, 5H), 3.96 (t, J=6.5, 2H), 3.77 (s, 3H), 3.68 (t,J=4.0 Hz, 2H), 3.05 (t, J=6.5 Hz, 2H), 2.21 (s, 6H), 2.08 (t, J=8.0 Hz,2H), 2.01 (s, 3H), 1.91 (s, 3H), 1.83-1.78 (m, 2H).

Example 368 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-N-(methylsulfonyl)benzamideI-368

In a scintillation vial,3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoicacid (15 mg, 0.023 mmol), EDC hydrochloride (10 mg, 0.052 mmol), andDMAP (3 mg, 0.025 mmol) were massed and dissolved in DCM (2 mL). After 5min, methanesulfonamide (10 mg, 0.11 mmol, 4.6 eq) was added, and thereaction was allowed to stir for 48 h, after which time it wasdetermined to be complete by LCMS analysis. The reaction was dilutedinto DCM/H₂O (20 mL, 1:1). The organic layer was separated, and theaqueous layer was extracted with DCM (2×5 mL). The combined organicextracts were dried with a phase separator and concentrated in vacuo.The crude product was dissolved in DMSO (1 mL) and purified by thereverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN 30-95% 0.1% TFA) toafford 2.0 mg (0.0019 mmol) of the title compound as a colorless oil. MS(ES) 736.2 (M+H).

Example 369 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-N-(cyclopropylsulfonyl)benzamideI-369

The title compound was prepared (1.8 mg, 0.0023 mmol) according toprocedures described in Example 367 using3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)benzoicacid (15 mg, 0.023 mmol, 1.0 eq) and substituting methanesulfonamidewith cyclopropanesulfonamide (10 mg, 0.083 mmol, 2.3 eq). MS (ES) 762.2(M+H).

Example 370 Preparation of3-bromo-5-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-370

The title compound was prepared (8.1 mg, 0.011 mmol, 83%) according toprocedures described in Example 314 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (6.8 mg, 0.013 mmol), ethyl 3-(aminomethyl)-5-bromobenzoatehydrochloride (5 mg, 0.017 mmol), HBTU (18 mg, 0.048 mmol),triethylamine (15 μL, 0.104 mmol), and DMF (1 mL); MS (ES) 711.1 (M+1).

Example 371 Preparation of(1r,4r)-4-((8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)methyl)cyclohexane-1-carboxylicacid I-371

To a solution of ethyl(1r,4r)-4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)cyclohexane-1-carboxylate (16.5 mg, 0.025 mmol) in DMF (0.5 mL)were added 1,3-dibromopropane (25 μL, 0.125 mmol), Cs₂CO₃ (81.5 mg, 0.25mmol) and the mixture was stirred at 80° C. for 3 h. The mixture wasfiltered, diluted with water (5 mL) and was extracted in CH₂Cl₂ (3×5mL). The organic layer was dried (anhyd. Na₂SO₄) and was evaporated. Toa solution of crude ester in THF (1 mL) at room temperature was added 2MLiOH (1 mL) the mixture was stirred at the ambient temperature for 5 h.The reaction mixture was evaporated, acidified to pH 7 with 4M HCl,extracted in EtOAc. The organic layer was dried, evaporated and finallypurified the reverse phase HPLC (Phenomenex Gemini C18, H₂O/CH₃CN 30-70%0.1% TFA) to afford the title compound (3.2 mg, 9%) as a white solid; MS(ES) 679.1 (M+H).

Example 372 Preparation of3-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-372

The title compound was prepared according to the procedures described inExample 373 using6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (12 mg, 0.020 mmol) and substituting methyl 4-(aminomethyl)benzoatewith methyl 3-(aminomethyl)benzoate (10 mg, 0.061 mmol) in Step C. MS(ES) 746.3 (M+H).

Example 373 Preparation of4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-373 Step A. Preparation of ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

In a 20-mL scintillation vial equipped with a stir bar, ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(30 mg, 0.057 mmol) was dissolved in DMF (3 mL), followed by addition ofsodium hydride (5 mg, 0.125 mmol). The reaction was allowed to stir for30 min at ambient temperature, followed by addition of4-(2-bromoethyl)morpholine hydrobromide (30 mg, 0.11 mmol). The reactionwas allowed to stir at ambient temperature for 3 h, after which time thereaction was determined to be complete by LCMS. The reaction mixture wasdiluted into DCM/H₂O (1:1, 20 mL). The -organic layer was separated, andthe aqueous layer was extracted with DCM (2×10 mL). The combined organicextracts were dried with a phase separator, and concentrated in vacuo.The crude material was carried forward to next step without furtherpurification. MS (ES) 641.2 (M+H).

Step B. Preparation of6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

In a 20-mL scintillation vial equipped with a stir bar, ethyl6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate(36 mg, 0.057 mmol) was dissolved in THF/H₂O/MeOH (4:1:1, 6 mL),followed by addition of lithium hydroxide (10 mg, 0.42 mmol). Thereaction was heated to 50° C. for 2 h, after which time the reaction wasdetermined to be complete by LCMS. The reaction mixture was concentratedin vacuo, then diluted with DCM/H₂O (1:1, 40 mL). The aqueous layer wasacidified with 1M HCl, and the layers were separated. The aqueous layerwas extracted with DCM (2×20 mL), and the combined organic extracts weredried over MgSO₄, filtered, and concentrated in vacuo to afford thetitle compound (32 mg, 0.52 mmol). MS (ES) 613.2 (M+H).

Step C. Preparation of methyl4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate

In a 2-dram vial equipped with a stir bar,6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid (12 mg, 0.020 mmol), HATU (10 mg, 0.026 mmol), and DIPEA (10 mg,0.078 mmol) were massed and dissolved in DMF (2 mL). The reaction wasallowed to stir for 10 min, followed by addition of methyl4-(aminomethyl)benzoate (10 mg, 0.061 mmol). The reaction was allowed tostir for 48 h, after which time the reaction was determined to becomplete by LCMS. The reaction was diluted into DCM/H₂O (20 mL, 1:1),and the organic layer was separated. The aqueous layer was extractedwith DCM (2×10 mL), and the combined organic layers were dried with aphase separator and then concentrated in vacuo. The crude material wasdissolved in DMSO (1 mL) and purified by reverse phase HPLC (PhenomenexGemini C18, H₂O/CH₃CN 30-95% 0.1% TFA) to give the title compound (10mg, 0.013 mmol). MS (ES) 760.3 (M+H).

Step D. Example 373

In a 2-dram vial equipped with a stir bar, methyl4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(3 mg, 0.0039 mmol) was dissolved in THF/H₂O/MeOH (4:1:1, 3 mL). Lithiumhydroxide was added (2 mg, 0.083 mmol), and the reaction was heated to50° C. for 4 h, after which time the reaction was determined to becomplete by LCMS. The reaction was concentrated in vacuo, and thendiluted into DCM/H₂O (1:1, 10 mL). The aqueous layer was acidified with1M HCl, and the organic layer was separated. The aqueous layer wasextracted with DCM (2×10 mL), and the combined organic extracts weredried with a phase separator, and concentrated in vacuo to afford thetitle compound (2 mg, 0.0027 mmol) as a colorless oil. MS (ES) 746.2(M+H).

Example 374 Preparation of4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-methyl-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoicacid I-374 Step A. Preparation of methyl4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-methyl-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate

In a 2-dram vial equipped with a stir bar, methyl4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(7 mg, 0.0092 mmol) was dissolved in DMF (2 mL). Sodium hydride (3 mg,0.075 mmol) was added, and the reaction was allowed to stir for 1 h atambient temperature. Methyl iodide (5 mg, 0.035 mmol) was added, and thereaction was allowed to stir for 1 h at ambient temperature. Thereaction was determined to be complete by LCMS, and then cooled to 0° C.and quenched with MeOH (0.1 mL). The reaction was then diluted intoDCM/H₂O (1:1, 20 mL), the organic layer was separated, and the aqueouslayer was extracted with DCM (2×10 mL). The combined organic extractswere dried with a phase separator and concentrated in vacuo. The crudematerial was carried forward without further purification. MS (ES) 774.3(M+H).

Step B. Example 374

In a 2-dram vial equipped with a stir bar, methyl4-((6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-methyl-1-(2-morpholinoethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxamido)methyl)benzoate(7 mg, 0.0092 mmol) was dissolved in THF/H₂O/MeOH (4:1:1, 3 mL). Lithiumhydroxide (2 mg, 0.083 mmol) was added, and the reaction was heated to50° C. for 2 h, after which time the reaction was determined to becomplete by LCMS. The reaction was concentrated, and the crude residuedissolved in DMSO (1 mL) and purified by reverse phase HPLC (PhenomenexGemini C18, H₂O/CH₃CN 30-95% 0.1% TFA) to give the title compound (2 mg,0.0026 mmol) as a colorless oil. MS (ES) 760.3 (M+H).

Example 375 Preparation of3-(8-chloro-11-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl)-1-methyl-1H-indazole-6-carboxylicacid I-375

This compound was synthesized according to the procedures described inExample 104 Step A and B using VU0659697 using methyl3-bromo-1-methyl-3a,7a-dihydro-1H-indazole-7-carboxylate; ¹H NMR (MeOD,400 MHz) δ (ppm) 8.28 (s, 1H), 7.81-7.75 (m, 3H), 7.29 (d, J=8.4 Hz,1H), 6.34 (s, 2H), 4.15 (t, J=6.4 Hz, 2H), 4.12 (s, 3H), 3.97 (t, J=6.4Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 3.87 (s, 3H), 3.26 (t, J=7.2 Hz, 2H),2.24 (s, 6H), 2.23-2.20 (m, 2H), 2.12 (s, 3H), 2.05 (s, 3H), 1.93-1.88(m, 2H); LCMS (ES) tR: 0.909 min (>99%, ELSD), m/z: 713.0 [M+1]

Example 377 Assays for Bcl-2 Family Proteins Activity

The in vitro modulation of Bcl-2 family proteins was determined asfollows.

Bak Peptide Binding Assay

General

Provided compounds of the present invention can be demonstrated tocompete for binding with fluorescently labeled peptides derived fromrelevant BH₃ domains. In some embodiments, a provided compound exhibitselectivity for Mcl-1 over Bcl-xL and Bcl-2.

Assay

Compound affinity was measured using a fluorescence polarizationanisotropy competition assay. Anisotropy measurements were carried outin 384-well, black, flat-bottom plates (Greiner Bio-one, Monroe, N.C.,USA). The assay was run using either a fluoresceinisothiocyanate-labeled BH₃ peptide derived from Bak(FITC-AHx-GQVGRQLAIIGDDINR-NH₂) or a fluorescein isothiocyanate-labeledBH₃ peptide derived from Bim (FITC-AHx-EARIAQELRRIGDEFNETYTR —NH₂) thatwere purchased from GenScript (Piscataway, N.J.) at >95% purity and usedwithout further purification. 10 nM FITC-Bak peptide and 15 nMrecombinant Mcl-1 (residues 172-327) were added to assay buffer (3 mMdithiothreitol, 50 mM NaCl, 20 mM Tris, pH 7.5). The Bim based assay wasrun with 1 nM FITC-Bim peptide and 1.5 nM recombinant Mcl-1 (residues172-327) added to assay buffer (20 mM TRIS pH 7.5, 50 mM NaCl, 3 mM DTT,0.01% CHAPS). For selectivity assays, 40 nM Bcl-2 (residues1-207^(A96T,G11OR), Δ35-91, replaced with Bcl-xL₃₅₋₅₀) or 4 nM Bcl-xL(residues 1-209, loop 45-86 deleted) were incubated with 10 nM FITC-Bakin assay buffer.

Compounds are diluted in DMSO in a 10-point, 3-fold serial dilutionscheme. For the FITC -BAK assay 2.5 uL compound is added to 47.5 μL ofassay buffer containing FITC-Bak and protein, for a final DMSOconcentration of 5% and a top concentration of 20 μM. A FITC-Bak peptidealone (100% inhibition) and peptide plus protein (0% inhibition) controlis included on each assay plate. For the FITC -Bim assay, compound isadded to 40 uL of assay buffer containing protein, 15 minutes prior toaddition of 10 μL of the FITC-Bim peptide, for a final DMSOconcentration of 0.165% and a top concentration of 200 nM. A FITC-Bimpeptide alone (100% inhibition) and peptide plus protein (0% inhibition)control is included on each assay plate. The plate was mixed andincubated for 90 minutes at room temperature. Anisotropy is measured atexcitation wavelength 480 nm and emission wavelength 535 nm using anEnVision Multi-label plate reader (PerkinElmer, Wellesley, Mass., USA)or a BioTek Cytation 3 (BioTek, Winooski, Vt., USA). Fluorescenceanisotropy is plotted against compound concentration to generate an IC₅₀(inhibitor concentration at which 50% of bound peptide is displaced) byfitting the data to a 4-parameter logistic model using XLFit software(Guildford, Surrey, UK). IC₅₀ is converted to a binding dissociationconstant (K_(i) value) according to the formula of Wang Z. FEBS Lett(1996) 3, 245.K _(i)=[I]₅₀/([L]₅₀ /K _(d)+[P]₀ /K _(d)+1)where [I]₅₀ is the concentration of the free inhibitor at 50%inhibition, [L]₅₀ is the concentration of the free labeled ligand at 50%inhibition, [P]₀ is the concentration of the free protein at 0%inhibition, K_(d) represents the dissociation constant of the FITCpeptide probe. The results for representative compounds are shown inTable 2 and 3.

TABLE 2 K_(i) for Examplified Compounds for Inhibition of Mcl-1 ExamplesK_(i) I-10, I-41, I-42, I-45, I-47, I-50, I-61, I-64, I-66, I-266,I-276, 10 μM-50 μM I-289, I-1, I-2, I-40, I-43, I-44, I-46, I-48, I-51,I-56, I-259, I-260, I-   1 μM-9.99 μM 261, I-264, I-265, I-272, I-275,I-278, I-288, I-3, I-9, I-11, I-12, I-52, I-54, I-67, I-262, I-313, 501nM-999 nM I-6, I-13, I-18, I-25, I-28, I-53, I-55, I-65, I-73, I-101,I-263, I- 301 nM-500 nM 268, I-279, I-4, I-5, I-7, I-8, I-15, I-16,I-17, I-19, I-20, I-21, I-22, I-24, I- 101 nM-299 nM 49, I-58, I-59,I-60, I-63, I-69, I-78, I-84, I-119, I-203, I-244, I-245, I-246, I-269,I-274, I-281, I-287 I-14, I-33, I-57, I-68, I-70, I-75, I-76, I-77,I-79, I-81, I-110, I-  51 nM-100 nM 112, I-164, I-194, I-202, I-204,I-296, I-297, I-308, I-312, I- 314, I-340, I-342, I-352, I-353, I-355,I-356, I-23, I-25a, I-26, I-27, I-29, I-30, I-31, I-32, I-34, I-35,I-36, I- <50 nM 37, I-38, I-39, I-62, I-66, I-71, I-72, I-74, I-80,I-82, I-83, I- 85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94,I-95, I- 96, I-97, I-98, I-99, I-100, I-102, I-103, I-104, I-105, I-106,I- 107, I-108, I-109, I-111, I-113, I-114, I-115, I-116, I-117, I- 118,I-120, I-121, I-122, I-123, I-124, I-125, I-126, I-127, I- 128, I-129,I-130, I-131, I-132, I-133, I-134, I-135, I-136, I- 137, I-138, I-139,I-140, I-141, I-142, I-143, I-144, I-145, I- 146, I-147, I-148, I-149,I-150, I-151, I-152, I-153, I-154, I- 155, I-156, I-157, I-158, I-159,I-160, I-161, I-162, I-163, I- 165, I-166, I-167, I-168, I-169, I-170,I-171, I-172, I-173, I- 174, I-175, I-176, I-177, I-178, I-179, I-180,I-181, I-182, I- 183, I-184, I-185, I-186, I-187, I-188, I-189, I-190,I-191, I- 192, I-193, I-195, I-196, I-197, I-198, I-199, I-200, I-201,I- 205, I-206, I-207, I-208, I-209, I-210, I-211, I-212, I-213, I- 214,I-215, I-216, I-217, I-218, I-219, I-220, I-221, I-222, I- 223, I-224,I-225, I-226, I-227, I-228, I-229, I-230, I-231, I- 232, I-233, I-234,I-235, I-236, I-237, I-238, I-239, I-240, I- 241, I-242, I-243, I-247,I-248, I-249, I-250, I-251, I-252, I- 253, I-254, I-255, I-256, 1257,I-258, I-267, I-270, I-271, I- 273, I-277, I-280, I-282, I-283, I-284,I-285, I-286, I-290, I- 291, I-292, I-293, I-294, I-295, I-298, I-299,I-300, I-301, I- 302, I-303, I-304, I-305, I-306, I-307, I-309, I-310,I-311, I- 315, I-316, I-317, I-318, I-319, I-320, I-321, I-322, I-323,I- 324, I-325, I-326, I-327, I-328, I-329, I-330, I-331, I-332, I- 333,I-334, I-335, I-336, I-337, I-338, I-339, I-341, I-343, I- 344, I-345,I-346, I-347, I-348, I-349, I-350, I-351, I-354, I- 357, I-358, I-359,I-360, I-361, I-362, I-363, I-364, I-365, I- 366, I-367, I-368, I-369,I-370, I-371, I-372, I-373, I-374, I- 375

TABLE 3 Mcl-1 Selectivity over Bcl-xL and Bcl-2 for RepresentativeCompounds. Example Mcl-1 K_(i) (nM) Bcl-xL K_(i) (nM) Bcl-2 K_(i) (nM)I-31 <7 6443 2200 I-32 <7 13430 3820 I-39 7.2 4590 1540 I-71 10 138505950 I-74 24 >100000 3540 I-80 <7 6750 2340 I-177 <7 8890 1900 I-181 <761500 3200 I-183 <7 14400 2900 I-188 <7 15600 5300 I-189 <7 4630 1370I-190 <7 45600 1640 I-280 <7 27000 7900

Among other things, these data demonstrate the utility of representativecompounds as selective inhibitors of the activity of Mcl-1 protein tobind peptides from relevant BH₃ domains.

Cellular Viability of Human Tumor Cell Lines

Human cancer cell lines ALMC-1, ALMC-2, K562, H929, and OPM-2 werecultured in media supplemented with 10% fetal bovine serum (FBS). Toevaluate compound effect on cellular proliferation, cells were plated at1,000 cells/well in 96-well tissue culture plates in a total volume of90 μL medium supplemented with 10% FBS (Sigma, Saint Louis, Mo.). 24hours later, 10 μL of compound (in a 2-fold serial dilution) is added tothe cells for a top concentration of 50 μM and a final DMSOconcentration <1%. After 72 hours, 50 μL of Cell TiterGlo (Promega,Madison, Wis., USA) reagent is added to each well and plates areincubated at room temperature, in the dark, for 30 minutes. Luminescenceis measured on a BioTek Cytation 3. Luminescence values are importedinto a template in XLFit (Guildford, Surrey, UK) that uses afour-parameter fit to generate an IC₅₀ value for each compound dilutionseries on the plate.

TABLE 4 IC₅₀ (in μM) for representative compounds on cellularproliferation of human cancer cell lines Compound ALMC-1 ALMC-2 H929OPM-2 K562 I-29 12.1 16.6 14 40 28.6 I-31 13.1 33.9 15 16.3 40 I-32 14.229.7 11.6 17.5 40 I-38 4.2 7.6 3.2 4.9 8.7 I-177 12.0 20.8 6.3 23.2I-178 6.1 8.7 8.7 11.7 11.8 I-220 4.9 14.8 I-236 6.9 12.2 7.3 7.2 25.0I-239 1.5 3.2 1.8 1.5 11.1 I-240 1.7 3.4 2.2 1.7 12.3Apoptosis Assay protocol (Caspase 3/7 Glo)

Induction of apoptosis was measured by quantifying caspase 3/7 activityusing the commercially available Caspase-Glo reagent (Promega, Madison,Wis., USA). This assay relies on the cleavage of a proluminescentsubstrate by activated caspases, which is then detected on the BioTekCytation 3. 5000 cells in 90 μL of media (+5% FBS) are plated in eachwell of a white 96-well plate and incubated overnight at 37′C in atissue culture incubator. The following day, compound is diluted in a10-pt, 2-fold serial dilution scheme for a final top concentration of 50μM. 10 μL of compound is added directly to the cell assay plate for afinal volume of 100 μL. Columns 11 and 12 are reserved for treatmentwith DMSO to serve as control wells. Plates are incubated for 3 hours.100 μL of Caspase-Glo reagent is added to each well and plates areincubated at room temperature, in the dark, for 30 minutes. Luminescenceis measured on the Cytation 3. Luminescence values are imported into atemplate in XLFit (Guildford, Surrey, UK) that uses a four-parameter fitto generate an IC₅₀ value for each compound dilution series on theplate.

TABLE 5 EC₅₀ (in μM) for representative compounds on cellular caspase3/7 activation of Mcl-1 sensitive human cancer cell lines. Compound H929I-80 3.1 I-175 2.3 I-177 2.3 I-178 3.1 I-184 10.0 I-201 1.6 I-239 0.75I-240 0.76 I-320 2.3

Among other things, these data demonstrate the utility of representativecompounds as inhibitors of cellular proliferation of human cancer celllines and initiators of apoptosis via caspase 3 and 7 activation in aMcl-1 sensitive human cancer cell line.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

We claim:
 1. A compound selected from any of formulae V or VII:

or a pharmaceutically acceptable salt thereof, wherein: L¹ is selectedfrom a covalent bond or an optionally substituted bivalent straight orbranched C₁₋₆ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with Cy; -Cy- is an optionallysubstituted bivalent ring independently selected from phenylene, 3-8membered saturated or partially unsaturated carbocyclylene, 5-6 memberedheteroarylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 3-8 membered saturated or partiallyunsaturated heterocyclylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; R¹ is selected from hydrogen,halogen, R, —OR, —SR, —S(O)R, —S(O)₂R, —S(O)₂N(R)₂, —N(R)₂, —C(O)N(R)₂,—C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,—N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)R^(x), —S(O)₂OH, —S(O)R^(y), or—S(O)₂R^(y); R^(2′) is selected from —C(O)-L⁴-R^(w), —C(O)N(R)-L⁴-R^(w),—C(O)N(R)—C(R)₂-L⁴-R^(w), or —C(O)S-L⁴-R^(w); L⁴ is an optionallysubstituted bivalent straight or branched C₁₋₈ hydrocarbon chain whereinone or more methylene units are optionally and independently replacedwith -Cy′-, —S—, —C(O)N(R)—, or —S(O)₂N(R)—; -Cy′- is an optionallysubstituted bivalent ring independently selected from phenylene, 3-8membered saturated or partially unsaturated carbocyclylene, 5-6 memberedheteroarylene having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 3-8 membered saturated or partiallyunsaturated heterocyclylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclicarylene or heteroarylene having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or an 8-10 membered saturated orpartially unsaturated heterocyclylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; R^(w) isselected from hydrogen, R, —OR, —SR, —S(O)R, —S(O)₂R, —S(O)₂N(R)₂,—N(R)₂, —C(O)N(R)₂, —C(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —N(R)S(O)₂N(R)₂, —C(O)OH, —C(O)OR, —C(O)R′, —S(O)₂OH, or—S(O)₂R^(y), or is selected from:

R^(x) is selected from —C(O)OR, —N(R)S(O)₂CF₃, —N(R)C(O)R, —N(R)C(O)OR,—N(R)C(O)N(R)₂, or —N(R)S(O)₂R; R^(y) is selected from —N(R)C(O)CF₃,—N(R)C(O)R, or —N(R)C(O)N(R)₂; each R is independently selected fromhydrogen or an optionally substituted group selected from C₁₋₁₂aliphatic or a ring selected from a 3-10 membered saturated or partiallyunsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclicsaturated, partially unsaturated or aryl ring, a 3-8 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated orpartially unsaturated heterocyclic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen or sulfur, or an 8-10membered bicyclic heteroaryl ring having 1-5 heteroatoms independentlyselected from nitrogen, oxygen or sulfur; each of R⁵ and R⁶ isindependently selected from R, halogen, —CN, —NO₂, —C(O)OR′, —OR′, —SR′,—C(O)N(R′)₂ —N(R′)₂, —S(O)₂N(R)₂, —N(R′)S(O)₂CF₃, —C(O)R′, N(R′)C(O)R′,—S(O)R′, —S(O)₂R′, —N(R′)C(O)OR′, and —N(R′)S(O)₂R′; R¹³ isindependently selected from R,

each R′ is independently selected from hydrogen or optionallysubstituted C₁₋₄ alkyl; and R⁷ is selected from hydrogen, halogen, —CN,—NO₂, —C(O)OR, —OCF₃, —OR, —SR, —S(O)₂OR, —P(O)(OH)₂, —C(O)N(R)₂,—N(R)₂, —S(O)₂N(R)₂, —N(R)S(O)₂CF₃, —C(O)N(R)S(O)₂R, —S(O)₂N(R)C(O)OR,—S(O)₂N(R)C(O)N(R)₂, —C(O)R, —C(O)N(R)S(O)₂CF₃, —N(R)C(O)R, —OC(O)R,—OC(O)N(R)₂, —C(NR)N(R)₂, —N(R)C(NR)N(R)₂, —S(O)R, —S(O)₂R, —N(R)C(O)OR,or —N(R)S(O)₂R, or an optionally substituted group selected from C₁₋₆aliphatic or a ring selected from a 3-8 membered saturated or partiallyunsaturated carbocyclic ring, phenyl, a 3-8 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, an 8-14 membered bicyclic or polycyclicsaturated, partially unsaturated or aryl ring, a 7-14 membered bicyclicor polycyclic saturated or partially unsaturated heterocyclic ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur.
 2. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁵ and R⁶ are each independently selected fromhydrogen or chlorine.
 3. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L⁴ is an optionally substitutedbivalent straight or branched C₁₋₈ hydrocarbon chain wherein one or moremethylene units are optionally and independently replaced with -Cy′- and-Cy′- is an optionally substituted bivalent phenylene ring.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L⁴ is an optionally substituted bivalent straight or branchedC₁₋₈ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy′- and -Cy′- is anoptionally substituted bivalent 3-8 membered saturated or partiallyunsaturated carbocyclylene ring.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L⁴ is an optionallysubstituted bivalent straight or branched C₁₋₈ hydrocarbon chain whereinone or more methylene units are optionally and independently replacedwith -Cy′- and -Cy′- is an optionally substituted bivalent 5-6 memberedheteroarylene ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.
 6. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L⁴ is an optionallysubstituted bivalent straight or branched C₁₋₈ hydrocarbon chain whereinone or more methylene units are optionally and independently replacedwith -Cy′- and -Cy′- is an optionally substituted bivalent 3-8 memberedsaturated or partially unsaturated heterocyclylene ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. 7.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L⁴ is an optionally substituted bivalent straight or branchedC₁₋₈ hydrocarbon chain wherein one or more methylene units areoptionally and independently replaced with -Cy′- and -Cy′- is anoptionally substituted bivalent 8-10 membered bicyclic arylene orheteroarylene ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein -Cy′- is an optionallysubstituted bivalent 8-10 membered saturated or partially unsaturatedheterocyclylene ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L⁴ is an optionallysubstituted bivalent straight or branched C₁₋₈ hydrocarbon chain whereinone or more methylene units are optionally and independently replacedwith -Cy′- and -Cy′- is an optionally substituted bivalent ring selectedfrom the following:


10. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(w) is selected from hydrogen, —R, —C(O)OH, —C(O)OR,or


11. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁷ is an optionally substituted group selected from thefollowing: pyrrolyl, pyrazolyl, pyridinyl,


12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹³ is selected from the following:


13. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 14. A method of inhibiting the activity of the Bcl-2family of proteins comprising administering to a mammalian patient inneed thereof a therapeutically effective amount of at least one compoundof claim 2, or a pharmaceutically acceptable salt thereof, and,optionally, an additional therapeutic agent selected from the group ofanti-cancer agents consisting of alkylating agents, angiogenesisinhibitors, antibodies, antimetabolites, antimitotics,antiproliferatives, aurora kinase inhibitors, Bcl-2 family proteininhibitors, Bcr-Abl kinase inhibitors, biologic response modifiers,cyclin-dependent kinase inhibitors, cell cycle inhibitors,cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2)receptor inhibitors, growth factor inhibitors, heat shock protein(HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonaltherapies, inhibitors of apoptosis proteins (IAPs), immunologicals,intercalating antibiotics, kinase inhibitors, mammalian target ofrapamycin inhibitors, mitogen-activated extracellular signal-regulatedkinase inhibitors, microRNA's, small inhibitory ribonucleic acids(siRNAs), non-steroidal anti-inflammatory drugs (NSAID's), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase inhibitors, proteasome inhibitors,purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors,retinoids, deltoids, plant alkaloids, and topoisomerase inhibitors. 15.A method of treating a disease or disorder associated with theexpression or over-expression of Mcl-1, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: the diseases or disorders are selected from the groupconsisting of leukemia, multiple myeloma, myeloma, pediatricbiphenotypic acute leukemia, and myelogenous leukemia.
 16. A method oftreating a disease or disorder associated with the expression orover-expression of anti-apoptotic Bcl-2 family protein memberscomprising administering to a mammalian patient in need of treatment atherapeutically effective amount of at least one compound of claim 1, ora pharmaceutically acceptable salt thereof, and, optionally, anadditional therapeutic agent wherein: (a) the diseases or disorders areselected from the group consisting of leukemia, multiple myeloma,myeloma, pediatric biphenotypic acute leukemia, and myelogenousleukemia; and (b) the additional therapeutic agent is selected from thegroup of anti-cancer agents consisting of alkylating agents,angiogenesis inhibitors, antibodies, antimetabolites, antimitotics,antiproliferatives, aurora kinase inhibitors, Bcl-2 family proteininhibitors, Bcr-Abl kinase inhibitors, biologic response modifiers,cyclin-dependent kinase inhibitors, cell cycle inhibitors,cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2)receptor inhibitors, growth factor inhibitors, heat shock protein(HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonaltherapies, inhibitors of apoptosis proteins (IAPs), immunologicals,intercalating antibiotics, kinase inhibitors, mammalian target ofrapamycin inhibitors, mitogen-activated extracellular signal-regulatedkinase inhibitors, microRNA's, small inhibitory ribonucleic acids(siRNAs), non-steroidal anti-inflammatory drugs (NSAID's), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase inhibitors, proteasome inhibitors,purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors,retinoids, deltoids, plant alkaloids, and topoisomerase inhibitors. 17.The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.